Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level

ABSTRACT

The present invention concerns combination of an amount of a GPR119 agonist with an amount of a dipeptidyl peptidase IV (DPP-IV) inhibitor such that the combination provides an effect in lowering a blood glucose level or in increasing a blood GLP-1 level in a subject over that provided by the amount of the GPR119 agonist or the amount of the DPP-IV inhibitor alone and the use of such a combination for treating or preventing diabetes and conditions related thereto or conditions ameliorated by increasing a blood GLP-1 level. The present invention also relates to the use of a G protein-coupled receptor to screen for GLP-1 secretagogues.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/328,405, filed onJan. 9, 2006, which in turn claims the benefit of U.S. Ser. Nos.60/643,086, filed Jan. 10, 2005, 60/683,172, filed May 19, 2005, and60/726,880, filed Oct. 14, 2005, each of which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for treatingor preventing diabetes and conditions related thereto. The presentinvention further relates to compositions and methods for increasing ablood GLP-1 level in a mammal. The present invention also relates tomethods of using a G protein-coupled receptor to screen for GLP-1secretagogues.

BACKGROUND OF THE INVENTION

The following discussion is intended to facilitate the understanding ofthe invention, but is not intended nor admitted to be prior art to theinvention.

A. Diabetes

Type 2 diabetes is one of the most common chronic diseases. Type 2diabetes is characterized by fasting and postprandial hyperglycemia andby relative insulin insufficiency. Hyperglycemia may cause long-termmicrovascular and macrovascular complications, such as nephropathy,neuropathy, retinopathy, and peripheral vascular disease. In addition,Type 2 diabetes is a comorbid disease that frequently compoundshyperlipidemia, atherosclerosis and hypertension. Hyperlipidemia is aprimary risk factor for cardiovascular disease due to atherosclerosis.Obesity is a well known common risk factor for the development ofatherosclerosis, stroke, hypertension and Type 2 diabetes. Type 2diabetes causes significant morbidity and mortality at considerableexpense to patients, their families and society. The incidence of Type 2diabetes in the United States is about 7% and accounts for as much as10% of all health care dollars. Furthermore, the incidence of Type 2diabetes worldwide is increasing such that Type 2 diabetes is nowconsidered to be a worldwide epidemic.

B. Glucagon-Like Peptide-1 (GLP-1)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from theposttranslaltional modification of proglucagon and secreted by gutendocrine cells. GLP-1 mediates its actions through a specific Gprotein-coupled receptor (GPCR), namely GLP-1R. GLP-1 is bestcharacterized as a hormone that regulates glucose homeostasis. GLP-1 hasbeen shown to stimulate glucose-dependent insulin secretion and toincrease pancreatic beta cell mass. GLP-1 has also been shown to reducethe rate of gastric emptying and to promote satiety. The efficacy ofGLP-1 peptide agonists in controlling blood glucose in Type 2 diabeticshas been demonstrated in several clinical studies [see, e.g., Nauck etal., Drug News Perspect (2003) 16:413-422], as has its efficacy inreducing body mass [Zander et al., Lancet (2002) 359:824-830].

GLP-1 receptor agonists are additionally useful in protecting againstmyocardial infarction and against cognitive and neurodegenerativedisorders. GLP-1 has been shown to be cardioprotective in a rat model ofmyocardial infarction [Bose et al., Diabetes (2005) 54:146-151], andGLP-1R has been shown in rodent models to be involved in learning andneuroprotection [During et al., Nat Med (2003) 9:1173-1179; and Greig etal., Ann N Y Acad Sci (2004) 1035:290-315].

Certain disorders such as Type 2 diabetes are characterized by adeficiency in GLP-1 [see, e.g., Nauck et al., Diabetes (2004) 53 Suppl3:S190-196].

Current GLP-1 peptide agonists suffer from a lack of oralbioavailability, negatively impacting patient compliance. Efforts todevelop orally bioavailable non-peptidergic, small-molecule agonists ofGLP-1R have so far been unsuccessful [Mentlein, Expert Opin InvestigDrugs (2005) 14:57-64]. An attractive alternative approach is to developan orally active composition for increasing an endogenous level of GLP-1in the blood.

C. GPR119

GPR119 G protein-coupled receptor (GPR119; e.g., human GPR119, GenBank®Accession No. AAP72125 and alleles thereof; e.g., mouse GPR119, GenBank®Accession No. AY288423 and alleles thereof) is selectively expressed onpancreatic beta cells. GPR119 activation leads to elevation of a levelof intracellular cAMP, consistent with GPR119 being coupled to Gs.Agonists to GPR119 stimulate glucose-dependent insulin secretion invitro and lower an elevated blood glucose level in vivo. See, e.g.,International Applications WO 04/065380, WO 04/076413, and EP 1338651,the disclosure of each of which is herein incorporated by reference inits entirety. In the patent literature, GPR119 has been referred to asRUP3 (see, e.g., International Application WO 00/31258).

D. Dipeptidyl Peptidase IV (DPP-IV)

Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) exhibits catalyticactivity against a broad range of peptide substrates that includespeptide hormones, neuropeptides, and chemokines. The incretinsglucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP), which stimulate glucose-dependent insulin secretionand otherwise promote blood glucose homeostasis, are rapidly cleaved byDPP-IV at the position 2 alanine leading to inactivation of theirbiological activity. Both pharmacological and genetic attenuation ofDPP-IV activity is associated with enhanced incretin action, increasedinsulin, and lower blood glucose in vivo. Genetic attenuation of DPP-IVactivity has been shown to provide resistance to obesity and to improveinsulin sensitivity. A second-generation DPP-IV inhibitor, LAF237 (Ahrenet al., J Clin Endocrinol Metab (2004) 89:2078-2084; and Villhauer etal., J Med Chem (2003) 46:2774-2789; the disclosure of each of which isherein incorporated by reference in its entirety), is currently in phase3 clinical trials for Type 2 diabetes and additional DPP-IV inhibitorsare in clinical development, including MK-0431, BMS-477118, PSN-9301 andSYR-322.

Because the incretin hormones are not the only substrates for DPP-IV,there is concern that inhibition of the cleavage of other endogenousDPP-IV substrates may give rise to undesirable side effects [see, e.g.,Chen et al, J Biol Regul Homeost Agents (2004) 18:47-54, the disclosureof which is herein incorporated by reference in its entirety]. Ittherefore would be advantageous to identify an activity promoting bloodglucose homeostasis which is associated with substantially lowerconcentrations of DPP-IV inhibitor.

E. G Protein-Coupled Receptors

GPCRs share a common structural motif, having seven sequences of between22 to 24 hydrophobic amino acids that form seven alpha helices, each ofwhich spans the membrane (each span is identified by number, i.e.,transmembrane-1 (TM-1), transmembrane-2 (TM-2), etc.). The transmembranehelices are joined by strands of amino acids between transmembrane-2 andtransmembrane-3, transmembrane-4 and transmembrane-5, andtransmembrane-6 and transmembrane-7 on the exterior, or “extracellular”side, of the cell membrane (these are referred to as “extracellular”regions 1, 2 and 3 (EC-1, EC-2 and EC-3), respectively). Thetransmembrane helices are also joined by strands of amino acids betweentransmembrane-1 and transmembrane-2, transmembrane-3 andtransmembrane-4, and transmembrane-5 and transmembrane-6 on theinterior, or “intracellular” side, of the cell membrane (these arereferred to as “intracellular” regions 1, 2 and 3 (IC-1, IC-2 and IC-3),respectively). The “carboxy” (“C”) terminus of the receptor lies in theintracellular space within the cell, and the “amino” (“N”) terminus ofthe receptor lies in the extracellular space outside of the cell.

Generally, when an agonist binds to a G protein-coupled receptor (oftenreferred to as “activation” of the receptor), there is a change in theconformation of the receptor that facilitates coupling between theintracellular region and an intracellular “G-protein.” It has beenreported that GPCRs are “promiscuous” with respect to G proteins, i.e.,that a GPCR can interact with more than one G protein. See, Kenakin, T.,43 Life Sciences 1095 (1988). Although other G proteins may exist,currently, Gq, Gs, Gi, Gz and Go are G proteins that have beenidentified. Ligand-activated GPCR coupling with the G-protein initiatesa signaling cascade process (referred to as “signal transduction”).Under normal conditions, signal transduction ultimately results incellular activation or cellular inhibition.

Gs stimulates the enzyme adenylyl cyclase. Gi (and Gz and Go), on theother hand, inhibit adenylyl cyclase. Adenylyl cyclase catalyzes theconversion of ATP to cAMP; thus, activated GPCRs that couple the Gsprotein are associated with increased cellular levels of cAMP. On theother hand, activated GPCRs that couple Gi (or Gz, Go) protein areassociated with decreased cellular levels of cAMP. See, generally,“Indirect Mechanisms of Synaptic Transmission,” Chpt. 8, From Neuron ToBrain (3^(rd) Ed.) Nichols, J. G. et al eds. Sinauer Associates, Inc.(1992). Thus, assays that detect cAMP can be utilized to determine if acandidate compound is, e.g., an agonist to the receptor (i.e., such acompound would increase the levels of cAMP). Gq and Go are associatedwith activation of the enzyme phospholipase C, which in turn hydrolyzesthe phospholipid PIP₂, releasing two intracellular messengers:diacyclglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). Increasedaccumulation of IP3 is associated with activation of Gq- andGo-associated receptors. See, generally, “Indirect Mechanisms ofSynaptic Transmission,” Chpt. 8, From Neuron To Brain (3^(rd) Ed.)Nichols, J. G. et al eds. Sinauer Associates, Inc. (1992). Assays thatdetect IP3 accumulation can be utilized to determine if a candidatecompound is, e.g., an agonist to a Gq- or Go-associated receptor (i.e.,such a compound would increase the levels of IP3). Assay that detect thelevel of intracellular free calcium can also be utilized to determine ifa candidate compound is, e.g., an agonist to a Gq or Go-associatedreceptor (i.e., such a compound would increase the levels ofintracellular free calcium) See, e.g., Table A (“N/A”: “notapplicable”). TABLE A Effect on cAMP Effect on IP3 Production uponAccumulation Effect on cAMP Activation of upon Activation ProductionGPCR (i.e., of GPCR (i.e., upon contact Effect on IP3 constitutiveconstitutive with an Accumulation upon activation or activation orInverse contact with an G protein agonist binding) agonist binding)Agonist Inverse Agonist Gs Increase N/A Decrease N/A Gi Decrease N/AIncrease N/A Gz Decrease N/A Increase N/A Go Decrease Increase IncreaseDecrease Gq N/A Increase N/A Decrease

There are also promiscuous G proteins, which appear to couple severalclasses of GPCRs to the phospholipase C pathway, such as Gα15 or Gα16[Offermanns & Simon, J Biol Chem (1995) 270:15175-80], or chimeric Gproteins designed to couple a large number of different GPCRs to thesame pathway, e.g. phospholipase C [Milligan & Rees, Trends inPharmaceutical Sciences (1999) 20:118-24].

Under physiological conditions, GPCRs exist in the cell membrane inequilibrium between two different conformations: an “inactive” state andan “active” state. A receptor in an inactive state is unable to link tothe intracellular signaling transduction pathway to initiate signaltransduction leading to a biological response. Changing the receptorconformation to the active state allows linkage to the transductionpathway (via the G-protein) and produces a biological response.

A receptor may be stabilized in an active state by a ligand or acompound such as a drug. Recent discoveries, including but notexclusively limited to modifications to the amino acid sequence of thereceptor, provide means other than ligands or drugs to promote andstabilize the receptor in the active state conformation. These meanseffectively stabilize the receptor in an active state by simulating theeffect of a ligand binding to the receptor. Stabilization by suchligand-independent means is termed “constitutive receptor activation.”An endogenous receptor exhibiting activity in the absence of ligand isreferred to as a constitutively active endogenous receptor.

SUMMARY OF THE INVENTION

The present invention concerns combination of an amount of a GPR119agonist with an amount of a dipeptidyl peptidase IV (DPP-IV) inhibitorsuch that the combination provides an effect in lowering a blood glucoselevel in a subject over that provided by the amount of the GPR119agonist or the amount of the DPP-IV inhibitor alone and the use of sucha combination for treating or preventing diabetes and conditions relatedthereto. The present invention further concerns combination of an amountof a GPR119 agonist with an amount of a dipeptidyl peptidase IV (DPP-IV)inhibitor such that the combination provides an effect in increasing ablood GLP-1 level in a subject over that provided by the amount of theGPR119 agonist or the amount of the DPP-IV inhibitor alone and the useof such a combination for treating or preventing a condition amelioratedby increasing a blood GLP-1 level or for increasing a blood GLP-1 levelin a subject deficient in GLP-1. The present invention also relates tomethods of using GPR119 G protein-coupled receptor to screen for GLP-1secretagogues.

In a first aspect, the present invention features a method of treatingor preventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a composition comprising or consisting essentially of a GPR119agonist and a DPP-IV inhibitor. In certain embodiments, the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto lower a blood glucose level in the subject. In certain embodiments,the blood glucose level is an elevated blood glucose level.

The present invention additionally features a method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof a GPR119 agonist and a DPP-IV inhibitor. In certain embodiments, theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to increase a blood GLP-1 level in the subject.

The present invention additionally features a method of increasing ablood GLP-1 level comprising administering to a subject deficient inGLP-1 a therapeutically effective amount of a composition comprising orconsisting essentially of a GPR119 agonist and a DPP-IV inhibitor. Incertain embodiments, the GPR119 agonist and the DPP-IV inhibitor areadministered in amounts sufficient to increase a blood GLP-1 level inthe subject.

In certain embodiments, diabetes is Type 2 diabetes.

In certain embodiments, the condition related to diabetes is selectedfrom the group consisting of hyperglycemia, impaired glucose tolerance,insulin resistance, pancreatic beta-cell insufficiency, enteroendocrinecell insufficiency, glucosuria, metabolic acidosis, cataracts, diabeticnephropathy, diabetic neuropathy, diabetic retinopathy, diabeticcoronary artery disease, diabetic cerebrovascular disease, diabeticperipheral vascular disease, metabolic syndrome, hyperlipidemia,atherosclerosis, stroke, hypertension, and obesity.

In certain embodiments, the condition ameliorated by increasing a bloodGLP-1 level is selected from the group consisting of diabetes, acondition related to diabetes, myocardial infarction, learningimpairment, memory impairment, and a neurodegenerative disorder.

In certain embodiments, the condition ameliorated by increasing a bloodGLP-1 level is a neurodegenerative disorder selected from the groupconsisting of excitotoxic brain damage caused by severe epilepticseizures, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, prion-associated disease, stroke, motor-neuron disease,learning or memory impairment, traumatic brain injury, spinal cordinjury, and peripheral neuropathy.

In certain embodiments, the subject is a human.

In a second aspect, the present invention features a compositioncomprising or consisting essentially of a GPR119 agonist and a DPP-IVinhibitor. In certain embodiments, the present invention relates to adosage form of the composition wherein the GPR119 agonist and the DPP-IVinhibitor are in amounts sufficient to lower a blood glucose level in asubject. In certain embodiments, the blood glucose level is an elevatedblood glucose level. In certain embodiments, the present inventionrelates to a dosage form of the composition wherein the GPR119 agonistand the DPP-IV inhibitor are in amounts sufficient to increase a bloodGLP-1 level in a subject.

In certain embodiments, the subject is a human.

In a third aspect aspect, the present invention features a compositioncomprising or consisting essentially of a GPR119 agonist and a DPP-IVinhibitor for use in a method of treatment of the human or animal bodyby therapy. In certain embodiments, the present invention relates to adosage form of the composition wherein the GPR119 agonist and the DPP-IVinhibitor are in amounts sufficient to lower a blood glucose level in asubject. In certain embodiments, the blood glucose level is an elevatedblood glucose level. In certain embodiments, the present inventionrelates to a dosage form of the composition wherein the GPR119 agonistand the DPP-IV inhibitor are in amounts sufficient to increase a bloodGLP-1 level in a subject.

The present invention additionally features a composition comprising orconsisting essentially of a GPR119 agonist and a DPP-IV inhibitor foruse in a method of treatment or prevention of diabetes or a conditionrelated thereto of the human or animal body by therapy. In certainembodiments, the present invention relates to a dosage form of thecomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to lower a blood glucose level in a subject. Incertain embodiments, the blood glucose level is an elevated bloodglucose level.

The present invention additionally features a composition comprising orconsisting essentially of a GPR119 agonist and a DPP-IV inhibitor foruse in a method of treatment or prevention of a condition ameliorated byincreasing a blood GLP-1 level of the human or animal body by therapy.In certain embodiments, the present invention relates to a dosage formof the composition wherein the GPR119 agonist and the DPP-IV inhibitorare in amounts sufficient to increase a blood GLP-1 level in a subject.

The present invention additionally features a composition comprising orconsisting essentially of a GPR119 agonist and a DPP-IV inhibitor foruse in a method of treatment or prevention of a deficiency of GLP-1 ofthe human or animal body by therapy. In certain embodiments, the presentinvention relates to a dosage form of the composition wherein the GPR119agonist and the DPP-IV inhibitor are in amounts sufficient to increase ablood GLP-1 level in a subject.

In certain embodiments, the subject is a human.

In a fourth aspect, the present invention features a method of preparinga pharmaceutical composition, said method comprising or consistingessentially of admixing a GPR119 agonist and a DPP-IV inhibitor,together with at least one pharmaceutically acceptable carrier. Incertain embodiments, the method further comprises the step of preparinga dosage form of the pharmaceutical composition wherein the GPR119agonist and the DPP-IV inhibitor are in amounts sufficient to lower ablood glucose level in a subject. In certain embodiments, the bloodglucose level is an elevated blood glucose level. In certainembodiments, the method further comprises the step of preparing a dosageform of the pharmaceutical composition wherein the GPR119 agonist andthe DPP-IV inhibitor are in amounts sufficient to increase a blood GLP-1level in a subject.

In certain embodiments, the subject is a human.

In a fifth aspect aspect, the present invention features apharmaceutical composition comprising or consisting essentially of aGPR119 agonist and a DPP-IV inhibitor, together with at least onepharmaceutically acceptable carrier. In certain embodiments, the presentinvention relates to a dosage form of the pharmaceutical compositionwherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to lower a blood glucose level in a subject. In certainembodiments, the blood glucose level is an elevated blood glucose level.In certain embodiments, the present invention relates to a dosage formof the pharmaceutical composition wherein the GPR119 agonist and theDPP-IV inhibitor are in amounts sufficient to increase a blood GLP-1level in a subject.

In certain embodiments, the subject is a human.

In a sixth aspect, the present invention features a method of treatingor preventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a pharmaceutical composition in accordance with the fifthaspect. In certain embodiments, the GPR119 agonist and the DPP-IVinhibitor are administered in amounts sufficient to lower a bloodglucose level in the subject. In certain embodiments, the blood glucoselevel is an elevated blood glucose level.

The present invention additionally features a method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a pharmaceutical composition in accordance with thefifth aspect. In certain embodiments, the GPR119 agonist and the DPP-IVinhibitor are administered in amounts sufficient to increase a bloodGLP-1 level in the subject.

The present invention additionally features a method of increasing ablood GLP-1 level comprising administering to a subject deficient inGLP-1 a therapeutically effective amount of a pharmaceutical compositionin accordance with the fifth aspect. In certain embodiments, the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto increase a blood GLP-1 level in the subject.

In certain embodiments, the subject is a human.

In a seventh aspect, the present invention features use of a compositioncomprising or consisting essentially of a GPR119 agonist and a DPP-IVinhibitor for the manufacture of a medicament for the treatment orprevention of diabetes or a condition related thereto. In certainembodiments, the present invention relates to a dosage form of themedicament wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to lower a blood glucose level in a subject. Incertain embodiments, the blood glucose level is an elevated bloodglucose level.

The present invention additionally features use of a compositioncomprising or consisting essentially of a GPR119 agonist and a DPP-IVinhibitor for the manufacture of a medicament for the treatment orprevention of a condition ameliorated by increasing a blood GLP-1 level.In certain embodiments, the present invention relates to a dosage formof the medicament wherein the GPR119 agonist and the DPP-IV inhibitorare in amounts sufficient to increase a blood GLP-1 level in a subject.

The present invention additionally features use of a compositioncomprising or consisting essentially of a GPR119 agonist and a DPP-IVinhibitor for the manufacture of a medicament for the treatment orprevention of a deficiency of GLP-1. In certain embodiments, the presentinvention relates to a dosage form of the medicament wherein the GPR119agonist and the DPP-IV inhibitor are in amounts sufficient to increase ablood GLP-1 level in a subject.

In certain embodiments, the subject is a human.

In an eighth aspect, the invention features a method for identifyingGLP-1 secretagogues or compounds useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level, comprising thesteps of:

-   -   (a) contacting a test compound with a host cell or with membrane        of a host cell that expresses a G protein-coupled receptor,        wherein the G protein-coupled receptor comprises an amino acid        sequence selected from the group consisting of:        -   (i) amino acids 1-335 of SEQ ID NO:2;        -   (ii) amino acids 2-335 of SEQ ID NO:2;        -   (iii) amino acids 2-335 of SEQ ID NO:2, with the proviso            that the receptor does not comprise the amino acid sequence            of SEQ ID NO:2;        -   (iv) the amino acid sequence of a G protein-coupled receptor            encoded by a polynucleotide comprising a nucleotide            sequence, said nucleotide sequence being the sequence            obtainable by a process comprising performing polymerase            chain reaction (PCR) on a human DNA sample using specific            primers SEQ ID NO:3 and SEQ ID NO:4;        -   (v) the amino acid sequence of a G protein-coupled receptor            encoded by a polynucleotide comprising a nucleotide            sequence, said nucleotide sequence hybridizing under            stringent conditions to the complement of SEQ ID NO:1; and        -   (vi) a biologically active fragment of any one of (i) to            (v); and    -   (b) determining the ability of the test compound to stimulate        functionality of the receptor;        wherein the ability of the test compound to stimulate        functionality of the receptor is indicative of the test compound        being a GLP-1 secretagogue or a compound useful for preventing        or treating a condition ameliorated by increasing a blood GLP-1        level.

The invention additionally features a method for identifying GLP-1secretagogues or compounds useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level, comprising steps (a) and(b) of this eighth aspect, and further comprising:

-   -   (c) contacting a compound which stimulates functionality of the        receptor in step (b) in vitro with a mammalian enteroendocrine        cell; and    -   (d) determining whether the compound stimulates GLP-1 secretion        from the mammalian enteroendocrine cell;        wherein the ability of the test compound to stimulate GLP-1        secretion from the mammalian enteroendocrine cell is indicative        of the test compound being a GLP-1 secretagogue or a compound        useful for treating or preventing a condition ameliorated by        increasing a blood GLP-1 level.

The invention additionally features a method for identifying GLP-1secretagogues or compounds useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level, comprising steps (a) and(b) of this eighth aspect, and further comprising:

-   -   (c) administering a compound which stimulates functionality of        the receptor in step (b) to a mammal; and    -   (d) determining whether the compound increases a blood GLP-1        level in the mammal;        wherein the ability of the test compound to increase a blood        GLP-1 level in the mammal is indicative of the test compound        being a GLP-1 secretagogue or a compound useful for treating or        preventing a condition ameliorated by increasing a blood GLP-1        level. In certain embodiments, the mammal is a non-human mammal.

In certain embodiments, the identified GLP-1 secretagogue or theidentified compound useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level is an agonist of thereceptor. In some embodiments, the agonist is a partial agonist.

In certain embodiments, the receptor is coupled to a G protein. Incertain embodiments, the G protein is Gs.

In certain embodiments, the human DNA sample is human genomic DNA.

In certain embodiments, the process is RT-PCR (reversetranscription-polymerase chain reaction). RT-PCR techniques are wellknown to the skilled artisan.

In certain embodiments, the human DNA sample is human cDNA. In certainembodiments, the cDNA is from a human tissue that expresses GPR119. Insome embodiments, the human tissue that expresses GPR119 is pancreas,pancreatic islet, colon, small intestine, or fetal liver. In certainembodiments, the cDNA is from a human cell type that expresses GPR119.In some embodiments, the cDNA is from a pancreatic beta cell line or anenteroendocrine cell line.

In certain embodiments, stringent hybridization conditions comprisehybridization at 42° C. in a solution comprising 50% formamide, 5×SSC(150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6),5× Denhardt's solution, 10% dextran sulfate, and 20 μg/ml denatured,sheared salmon sperm DNA, followed by washing at 65° C. in a solutioncomprising 0.1×SSC. Hybridization techniques are well known to theskilled artisan.

In certain embodiments, the G protein-coupled receptor encoded by apolynucleotide comprising a nucleotide sequence, said nucleotidesequence hybridizing under stringent conditions to the complement of SEQID NO:1, exhibits a biological activity selected from the groupconsisting of increasing a level of intracellular cAMP and binding aknown ligand of GPR119. In certain embodiments, the encoded Gprotein-coupled receptor increases a level of intracellular cAMP andbinds a known ligand of GPR119.

In some embodiments, the G protein-coupled receptor is part of a fusionprotein comprising a G protein. Techniques for making a GPCR:G fusionconstruct are well known to the skilled artisan (see, e.g.,International Application WO 02/42461).

In some embodiments, the G protein-coupled receptor is recombinant.

In certain embodiments, the host cell comprises an expression vector,said expression vector comprising a polynucleotide encoding the Gprotein-coupled receptor. In some embodiments, the expression vector ispCMV. This vector was deposited with the American Type CultureCollection (ATCC) on Oct. 13, 1998 (10801 University Blvd., Manassas,Va. 20110-2209 USA) under the provisions of the Budapest Treaty for theInternational Recognition of the Deposit of Microorganisms for thePurpose of Patent Procedure. The DNA was tested by the ATCC anddetermined to be viable. The ATCC has assigned the following depositnumber to pCMV: ATCC #203351. Other suitable expression vectors will bereadily apparent to those of ordinary skill in the art, and a widevariety of expression vectors are commercially available (e.g., fromClontech, Palo Alto, Calif.; Stratagene, La Jolla, Calif.; andInvitrogen, Carlsbad, Calif.).

In some embodiments, the host cell is mammalian. In some embodiments,the mammalian host cell is selected from the group consisting of 293,293T, CHO, MCB3901, and COS-7. In some embodiments, the host cell ismelanophore. In some embodiments, the host cell is an enteroendocrinecell. In some embodiments, the enteroendocrine cell is GLUTag-Fro cellline. Other suitable host cells will be readily apparent to those ofordinary skill in the art, and a wide variety of cell lines areavailable from the American Type Culture Collection, 10801 UniversityBoulevard, Manassas, Va. 20110-2209.

In certain embodiments, said determining is consistent with the Gprotein-coupled receptor being a Gs-coupled receptor.

In some embodiments, said determining is consistent with the Gprotein-coupled receptor being coupled through a promiscuous G protein,such as Gα15 or Gα16, to the phopholipase C pathway. Promiscuous Gproteins are well known to the skilled artisan [see, e.g., Offermanns etal., J Biol Chem (1995) 270:15175-15180]. In some embodiments, saiddetermining is consistent with the G protein-coupled receptor beingcoupled through a chimeric G protein, e.g. to the phospholipase Cpathway. Chimeric G proteins are well known to the skilled artisan [see,e.g., Milligan et al., Trends in Pharmaceutical Sciences (1999)20:118-124; and WO 02/42461].

In some embodiments, said determining is through the measurement of alevel of a second messenger selected from the group consisting of cyclicAMP (cAMP), cyclic GMP (cGMP), inositol 1,4,5-triphosphate (IP3),diacylglycerol (DAG), MAP kinase activity, MAPK/ERK kinase kinase-1(MEKK1) activity, and Ca2+. In some preferred embodiments, the secondmessenger is cAMP. In certain preferred embodiments, a level ofintracellular cAMP is elevated.

In certain embodiments, said determining is carried out with membranecomprising the G protein-coupled receptor.

In certain embodiments, said determining is through the use of amelanophore assay. In some preferred embodiments, a level of pigmentdispersion is elevated.

In some embodiments, said determining is through the measurement of anactivity mediated by elevation of a level of intracellular cAMP. In someembodiments, said activity is stimulation of GLP-1 secretion.

In some embodiments, said determining is through CRE-Luc reporter assay.In some preferred embodiments, a level of luciferase activity iselevated.

In some embodiments, said determining is through the measurement ofGTPγS binding to membrane comprising the G protein-coupled receptor. Insome preferred embodiments, said GTPγS is labeled with [³⁵S]. In somepreferred embodiments, said GTPγS binding to membrane comprising theGPCR is elevated.

In some embodiments, the test compound is a small molecule. In someembodiments, the test compound is a small molecule, with the provisothat the small molecule is not a polypeptide. In some embodiments, thetest compound is a small molecule, with the proviso that the smallmolecule is not an antibody or an antigen-binding fragment thereof. Insome embodiments, the test compound is a small molecule, with theproviso that the small molecule is not a lipid. In some embodiments, thetest compound is a small molecule, with the proviso that the smallmolecule is not a polypeptide or a lipid. In some embodiments, the testcompound is a polypeptide. In some embodiments, the test compound is apolypeptide, with the proviso that the polypeptide is not an antibody oran antigen-binding fragment thereof. In some embodiments, the testcompound is a lipid. In some embodiments, the test compound is not anantibody or an antigen-binding fragment thereof. In some embodiments,the test compound is an antibody or an antigen-binding fragment thereof.

In some embodiments, the method further comprises synthesizing the GLP-1secretagogue or the compound useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level.

In some embodiments, the method further comprises: optionally,determining the structure of the GLP-1 secretagogue or the compounduseful for treating or preventing a condition ameliorated by increasinga blood GLP-1 level; and providing the GLP-1 secretagogue or thecompound useful for treating or preventing a condition ameliorated byincreasing a blood GLP-1 level or providing the name or structure of theGLP-1 secretagogue or the compound useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level.

In some embodiments, said method further comprises: optionally,determining the structure of the GLP-1 secretagogue or the compounduseful for treating or preventing a condition ameliorated by increasinga blood GLP-1 level; optionally, providing the name or structure of theGLP-1 secretagogue or the compound useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level; and producingor synthesizing the GLP-1 secretagogue or the compound useful fortreating or preventing a condition ameliorated by increasing a bloodGLP-1 level.

In some embodiments, said method further comprises the step offormulating the GLP-1 secretagogue or the compound useful for treatingor preventing a condition ameliorated by increasing a blood GLP-1 levelinto a pharmaceutical composition.

In a ninth aspect, the invention features a method for identifying GLP-1secretagogues or compounds useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level, comprising the steps of:

-   -   (a) contacting a G protein-coupled receptor with an optionally        labeled known ligand to the receptor in the presence or absence        of a test compound, wherein the G protein-coupled receptor        comprises an amino acid sequence selected from the group        consisting of:        -   (i) amino acids 1-335 of SEQ ID NO:2;        -   (ii) amino acids 2-335 of SEQ ID NO:2;        -   (iii) amino acids 2-335 of SEQ ID NO:2, with the proviso            that the receptor does not comprise the amino acid sequence            of SEQ ID NO:2;        -   (iv) the amino acid sequence of a G protein-coupled receptor            encoded by a polynucleotide comprising a nucleotide            sequence, said nucleotide sequence being the sequence            obtainable by a process comprising performing polymerase            chain reaction (PCR) on a human DNA sample using specific            primers SEQ ID NO:3 and SEQ ID NO:4;        -   (v) the amino acid sequence of a G protein-coupled receptor            encoded by a polynucleotide comprising a nucleotide            sequence, said nucleotide sequence hybridizing under            stringent conditions to the complement of SEQ ID NO:1; and        -   (vi) a biologically active fragment of any one of (i) to            (v); and    -   (b) detecting the complex between said known ligand and said        receptor; and    -   (c) determining whether less of said complex is formed in the        presence of the test compound than in the absence of the test        compound;        wherein said determination is indicative of the test compound        being a GLP-1 secretagogue or a compound useful for preventing        or treating a condition ameliorated by increasing a blood GLP-1        level.

In certain embodiments, the optionally labeled known ligand is a labeledknown ligand. In certain embodiments, the labeled known ligand is aradiolabeled known ligand. Techniques for radiolabeling a compound, suchas for labeling a known ligand of a G protein-coupled receptor of theinvention, are well known to the skilled artisan. See, e.g.,International Application WO 04/065380.

Techniques for detecting the complex between a G protein-coupledreceptor and a compound known to be a ligand of the G protein-coupledreceptor are well known to the skilled artisan. See, e.g., InternationalApplication WO 04/065380.

The invention additionally features a method for identifying GLP-1secretagogues or compounds useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level, comprising steps (a) to(c) of this ninth aspect, and further comprising:

-   -   (d) contacting a compound in the presence of which less of said        complex is formed in step (c) in vitro with a mammalian        enteroendocrine cell; and    -   (e) determining whether the compound stimulates GLP-1 secretion        from the mammalian enteroendocrine cell;        wherein the ability of the test compound to stimulate GLP-1        secretion from the mammalian enteroendocrine cell is indicative        of the test compound being a GLP-1 secretagogue or a compound        useful for treating or preventing a condition ameliorated by        increasing a blood GLP-1 level.

The invention additionally features a method for identifying GLP-1secretagogues or compounds useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level, comprising steps (a) to(c) of this ninth aspect, and further comprising:

-   -   (d) administering a compound in the presence of which less of        said complex is formed in step (c) to a mammal; and    -   (e) determining whether the compound increases a blood GLP-1        level in the mammal;        wherein the ability of the test compound to increase a blood        GLP-1 level in the mammal is indicative of the test compound        being a GLP-1 secretagogue or a compound useful for treating or        preventing a condition ameliorated by increasing a blood GLP-1        level. In certain embodiments, the mammal is a non-human mammal.

In certain embodiments, the receptor is recombinant.

In some embodiments, the test compound is a small molecule. In someembodiments, the test compound is a small molecule, with the provisothat the small molecule is not a polypeptide. In some embodiments, thetest compound is a small molecule, with the proviso that the smallmolecule is not an antibody or an antigen-binding fragment thereof. Insome embodiments, the test compound is a small molecule, with theproviso that the small molecule is not a lipid. In some embodiments, thetest compound is a small molecule, with the proviso that the smallmolecule is not a polypeptide or a lipid. In some embodiments, the testcompound is a polypeptide. In some embodiments, the test compound is apolypeptide, with the proviso that the polypeptide is not an antibody oran antigen-binding fragment thereof. In some embodiments, the testcompound is a lipid. In some embodiments, the test compound is not anantibody or an antigen-binding fragment thereof. In some embodiments,the test compound is an antibody or an antigen-binding fragment thereof.

In some embodiments, the method further comprises synthesizing the GLP-1secretagogue or the compound useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level.

In some embodiments, the method further comprises: optionally,determining the structure of the GLP-1 secretagogue or the compounduseful for treating or preventing a condition ameliorated by increasinga blood GLP-1 level; and providing the GLP-1 secretagogue or thecompound useful for treating or preventing a condition ameliorated byincreasing a blood GLP-1 level or providing the name or structure of theGLP-1 secretagogue or the compound useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level.

In some embodiments, said method further comprises: optionally,determining the structure of the GLP-1 secretagogue or the compounduseful for treating or preventing a condition ameliorated by increasinga blood GLP-1 level; optionally, providing the name or structure of theGLP-1 secretagogue or the compound useful for treating or preventing acondition ameliorated by increasing a blood GLP-1 level; and producingor synthesizing the GLP-1 secretagogue or the compound useful fortreating or preventing a condition ameliorated by increasing a bloodGLP-1 level.

In some embodiments, said method further comprises the step offormulating the GLP-1 secretagogue or the compound useful for treatingor preventing a condition ameliorated by increasing a blood GLP-1 levelinto a pharmaceutical composition.

This application claims the benefit of priority from the followingprovisional applications, filed via U.S. Express mail with the UnitedStates Patent and Trademark Office on the indicated dates: U.S.Provisional No. 60/643,086, filed Jan. 10, 2005; U.S. Provisional No.60/683,172, filed May 19, 2005; and U.S. Provisional No. 60/726,880,filed Oct. 14, 2005. The disclosure of each of the foregoingapplications is herein incorporated by reference in its entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated in connection with the figures appendedhereto in which:

FIG. 1 shows a synergistic effect of GPR119 agonist and DPP-IV inhibitorin lowering an elevated blood glucose level in oral glucose tolerancetest (oGTT) in mice. See Example 1.

FIG. 2 shows a synergistic effect of GPR119 agonist and DPP-IV inhibitorin increasing a blood GLP-1 level after glucose challenge in mice. SeeExample 3.

FIG. 3 shows expression of GPR119 in gut. See Example 10.

FIG. 4 shows expression of GPR119 in GLUTag enteroendocrine cell line.See Example 11.

FIG. 5 shows elevation of the level of intracellular cAMP in GLUTagenteroendocrine cells by GPR119 agonist. See Example 12.

FIG. 6 shows stimulation of GLP-1 secretion in GLUTag enterendocrinecells by GPR119 agonist. See Example 13.

FIG. 7 shows an effect of GPR119 agonist AR244061 and DPP-IV inhibitorMK-0431 in lowering blood glucose level in oral glucose tolerance test(oGTT) in mice. See Example 14.

FIG. 8 shows an effect of GPR119 agonist AR244061 and DPP-IV inhibitorLAF237 in lowering blood glucose level in oral glucose tolerance test(oGTT) in mice. See Example 14.

FIG. 9 shows an effect of GPR119 agonist AR244061 and DPP-IV inhibitorFE107542 in lowering blood glucose level in oral glucose tolerance test(oGTT) in mice. See Example 14.

DETAILED DESCRIPTION OF THE INVENTION

This invention is concerned with the combination of certain compounds,or pharmaceutically acceptable salts thereof, for the treatment orprevention of diabetes and conditions related thereto. This invention isfurther concerned with the combination of certain compounds, orpharmaceutically acceptable salts thereof, for the treatment orprevention of a condition ameliorated by increasing a blood GLP-1 level.Applicant has found that an amount of a GPR119 agonist in combinationwith an amount of a DPP-IV inhibitor can provide an unexpectedsynergistic effect in lowering a blood glucose level in a subject overthat provided by the amount of the GPR119 agonist alone or by the amountof the DPP-IV inhibitor alone. Applicant has additionally found that anamount of a GPR119 agonist in combination with an amount of a DPP-IVinhibitor can provide an unexpected synergistic effect in increasing ablood GLP-1 level in a subject over that provided by the amount of theGPR119 agonist alone or by the amount of the DPP-IV inhibitor alone.Applicant has additionally discovered that GPR119 is a GLP-1secretagogue receptor.

By the use of a combination of a GPR119 agonist and a DPP-IV inhibitorin accordance with the present invention, it is possible to treat orprevent diabetes and conditions related thereto with a dose of a DPP-IVinhibitor substantially lower than that currently contemplated for usein therapy for diabetes and conditions related thereto, thereby reducingthe likelihood of unwanted side-effects associated with inhibition ofDPP-IV activity. By the use of a combination of a GPR119 agonist and aDPP-IV inhibitor in accordance with the present invention, it ispossible to treat or prevent a condition ameliorated by increasing ablood GLP-1 level with a dose of a DPP-IV inhibitor substantially lowerthan that currently contemplated for use in therapy for said condition,thereby reducing the likelihood of unwanted side-effects associated withinhibition of DPP-IV activity. Furthermore, by the use of a combinationof a GPR119 agonist and a DPP-IV inhibitor in accordance with thepresent invention, it is possible to treat or prevent diabetes andconditions related thereto with a dose of a GPR119 agonist substantiallylower than that currently contemplated for use in therapy for diabetesand conditions related thereto, thereby reducing the likelihood ofunwanted side-effects should any be found to be associated withactivation of GPR119 receptor. The present invention provides a new,unexpected and advantageous approach to lowering a blood glucose levelin a subject. The present invention additionally provides a new,unexpected and advantageous approach to increasing a blood GLP-1 levelin a subject.

The term “ligand”, as used herein, shall mean a molecule thatspecifically binds to a GPCR. A ligand may be, for example, apolypeptide, a lipid, a small molecule, an antibody. An endogenousligand is a ligand that is an endogenous, natural ligand for a nativeGPCR. A ligand may be a GPCR “antagonist”, “agonist”, “partial agonist”,or “inverse agonist”, or the like.

The term “agonist”, as used herein, shall mean an agent (e.g., ligand,candidate compound) that by virtue of binding to a GPCR activates theGPCR so as to elicit an intracellular response mediated by the GPCR.

The term “partial agonist”, as used herein, shall mean an agent (e.g.,ligand, candidate compound) that by virtue of binding to a GPCRactivates the GPCR so as to elicit an intracellular response mediated bythe GPCR, albeit to a lesser exent or degree than does a full agonist.

The term “antagonist” shall mean an agent (e.g., ligand, candidatecompound) that binds, and preferably binds competitively, to a GPCR atabout the same site as an agonist or partial agonist but which does notactivate an intracellular response initiated by the active form of theGPCR, and can thereby inhibit the intracellular response by agonist orpartial agonist. An anatagonist typically does not diminish the baselineintracellular response in the absence of an agonist or partial agonist.

The term “inverse agonist” shall mean an agent (e.g., ligand, candidatecompound) which binds to a GPCR and which inhibits the baselineintracellular response initiated by the active form of the receptorbelow the normal base level activity which is observed in the absence ofan agonist or partial agonist.

The term “GPR119 agonist,” as used herein, refers to a compound thatbinds to GPR119 receptor and acts as an agonist.

The term “selective GPR119 agonist,” as used herein, refers to a GPR119agonist having selectivity for GPR119 receptor over one or more closelyrelated receptors, such as corticotrophin-releasing factor-1 (CRF-1)receptor.

The term “DPP-IV inhibitor,” as used herein, refers to a compound thatbinds to DPP-IV and inhibits DPP-IV dipeptidyl peptidase activity.

The term “selective DPP-IV inhibitor,” as used herein, refers to aDPP-IV inhibitor having selectivity for DPP-IV over closely relatedpeptidases, such as one or more of post-proline-cleaving enzyme (PPCE),dipeptidyl peptidase II (DPP-II), dipeptidyl peptidase 8 (DPP-8), anddipeptidyl peptidase 9 (DPP-9).

The term “blood glucose level” or “blood GLP-1 level” shall mean bloodglucose concentration or blood GLP-1 concentration, respectively. Incertain embodiments, blood GLP-1 level is a level in blood ofbiologically active GLP-1, wherein GLP-1 having agonist activity atGLP-1R is biologically active. In certain embodiments, a blood glucoselevel or blood GLP-1 level is a plasma glucose level or a plasma GLP-1level.

The term “elevated blood glucose level” shall mean an elevated bloodglucose level such as that found in a subject demonstrating clinicallyinappropriate basal and postprandial hyperglycemia or such as that foundin a subject in oral glucose tolerance test (oGTT).

The term “subject,” as used herein, shall refer to a mammal, includingbut not limited to a mouse, a rat, a rabbit, a pig, a dog, a cat, anon-human primate and a human, more preferably to a mouse or rat, mostpreferably to a human.

The term “in need of prevention or treatment” as used herein refers to ajudgement made by a caregiver (e.g. physician, nurse, nurse practitionerin the case of humans; veterinarian in the case of non-human mammals)that a subject requires or will benefit from treatment.

The term “therapeutically effective amount” or “therapeuticallyeffective dose” is intended to mean that amount of drug that will elicitthe desired biological or medical response. In certain embodiments, atherapeutically effective amount is that amount of drug which willcreate an AUC inhibition above 30% in mouse oGTT assay.

The term “therapeutically ineffective amount” or “therapeuticallyineffective dose” is intended to mean an amount of drug less than thetherapeutically effective amount of the drug. In certain embodiments, atherapeutically ineffective amount is an amount of drug which willcreate an AUC inhibition less than or equal to 30% in mouse oGTT assay.

The term “amount that is effective to prevent” refers to that amount ofdrug that will prevent or reduce the risk of occurrence of thebiological or medical event that is sought to be prevented. In manyinstances, the amount that is effective to prevent is the same as thetherapeutically effective amount.

The term “composition” shall mean a material comprising at least onecomponent.

The term “active ingredient” shall mean any component that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation and treatment in a mammal.

The term “dosage form” shall mean the physical form in which a drug isproduced and dispensed, such as a tablet, capsule, or an injectable.

As used herein, the term “diabetes” encompasses both insulin-dependentdiabetes mellitus (also known as Type 1 diabetes) andnon-insulin-dependent diabetes mellitus (also known as Type 2 diabetes).

The term “condition related to diabetes” is intended to include but notbe limited to hyperglycemia, impaired glucose tolerance, insulinresistance, pancreatic beta-cell insufficiency, enteroendocrine cellinsufficiency, glucosuria, metabolic acidosis, cataracts, diabeticnephropathy, diabetic neuropathy, diabetic retinopathy, diabeticcoronary artery disease, diabetic cerebrovascular disease, diabeticperipheral vascular disease, metabolic syndrome, hyperlipidemia,atherosclerosis, stroke, hypertension, and obesity, where it isunderstood that conditions related to diabetes can be included inembodiments individually or in any combination.

The term “condition ameliorated by increasing a blood GLP-1 level” isintended to include but not be limited to diabetes, a condition relatedto diabetes, myocardial infarction, learning impairment, memoryimpairment, and a neurodegenerative disorder, where it is understoodthat conditions ameliorated by increasing a blood GLP-1 level can beincluded in embodiments individually or in any combination.

The term “atherosclerosis” as used herein refers to a form of vasculardisease characterized by the deposition of atheromatous plaquescontaining cholesterol and lipids on the innermost layer of the walls oflarge and medium-sized arteries.

The term “metabolic syndrome” as defined herein, and according to theAdult Treatment Panel III (ATP III; National Institutes of Health: ThirdReport of the National Cholesterol Education Program Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III), Executive Summary; Bethesda, Md., NationalInstitutes of Health, National Heart, Lung and Blood Institute, 2001(NIH pub. No 01-3670), occurs when a person meets three or more of fivecriteria related to obesity, hypertriglyceridemia, low HDL cholesterol,high blood pressure, and high fasting glucose.

The term “neurodegenerative disorder” is intended to include but not belimited to excitotoxic brain damage caused by severe epileptic seizures,Alzheimer's disease, Parkinson's disease, Huntington's disease,prion-associated disease, stroke, motor-neuron disease, learning ormemory impairment, traumatic brain injury, spinal cord injury, andperipheral neuropathy.

The term “obesity,” as used herein, is defined as a body mass index(BMI) of 30.0 or greater, in accordance with the WHO classifications ofweight [Kopelman, Nature (2000) 404:635-643; the disclosure of which isherein incorporated by reference in its entirety].

The term “C₁₋₅ acyl” denotes a C₁₋₅ alkyl radical attached to a carbonylwherein the definition of alkyl has the same definition as describedherein; some examples include but not limited to, acetyl, propionyl,n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e., pivaloyl),pentanoyl and the like.

The term “C₁₋₅ acyloxy” denotes an acyl radical attached to an oxygenatom wherein acyl has the same definition has described herein; someexamples include but not limited to acetyloxy, propionyloxy,butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and thelike.

The term “C₁₋₆ acylsulfonamide” refers to a C₁₋₆ acyl attached directlyto the nitrogen of the sulfonamide, wherein the definitions for C₁₋₆acyl and sulfonamide have the same meaning as described herein, and aC₁₋₆ acylsulfonamide can be represented by the following formula:

Some embodiments of the present invention are when acylsulfonamide is aC₁₋₅ acylsulfonamide, some embodiments are C₁₋₄ acylsulfonamide, someembodiments are C₁₋₃ acylsulfonamide, and some embodiments are C₁₋₂acylsulfonamide. Examples of an acylsulfonamide include, but not limitedto, acetylsulfamoyl [—S(═O)₂NHC(═O)Me], propionylsulfamoyl[—S(═O)₂NHC(═O)Et], isobutyrylsulfamoyl, butyrylsulfamoyl,2-methyl-butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl,2,2-dimethyl-propionylsulfamoyl, pentanoylsulfamoyl,2-methyl-pentanoylsulfamoyl, 3-methyl-pentanoylsulfamoyl,4-methyl-pentanoylsulfamoyl, and the like.

The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present, someembodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, andsome embodiments have 2 carbons. Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls. Accordingly, if more than one double bond is present thenthe bonds may be all E or Z or a mixtures of E and Z. Examples of analkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl and the like.

The term “C₁₋₄ alkoxy” as used herein denotes a radical alkyl, asdefined herein, attached directly to an oxygen atom. Examples includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “C₁₋₈ alkyl” denotes a straight or branched carbon radicalcontaining 1 to 8 carbons, some embodiments are 1 to 6 carbons, someembodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons.Examples of an alkyl include, but not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl,iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “C₁₋₄ alkylcarboxamido” or “C₁₋₄ alkylcarboxamide” denotes asingle C₁₋₄ alkyl group attached to the nitrogen of an amide group,wherein alkyl has the same definition as found herein. The C₁₋₅alkylcarboxamido may be represented by the following:

Examples include, but not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁₋₃ alkylene” refers to a C₁₋₃ divalent straight carbongroup. In some embodiments C₁₋₃ alkylene refers to, for example, —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, and the like. In some embodiments, C₁₋₃ alkylenerefers to —CH—, —CHCH₂—, —CHCH₂CH₂—, and the like wherein these examplesrelate generally to “A”.

The term “C₁₋₄ alkylsulfinyl” denotes a C₁₋₄ alkyl radical attached to asulfoxide radical of the formula: —S(O)— wherein the alkyl radical hasthe same definition as described herein. Examples include, but notlimited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,iso-butylsulfinyl, t-butyl, and the like.

The term “C₁₋₄ alkylsulfonamide” refers to the groups

wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₄ alkylsulfonyl” denotes a C₁₋₄ alkyl radical attached to asulfone radical of the formula: —S(O)₂— wherein the alkyl radical hasthe same definiti+on as described herein. Examples include, but notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, t-butyl, and the like.

The term “C₁₋₄ alkylthio” denotes a C₁₋₄ alkyl radical attached to asulfide of the formula: —S— wherein the alkyl radical has the samedefinition as described herein. Examples include, but not limited to,methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, n-propylsulfanyl,iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,iso-butylsulfanyl, t-butyl, and the like.

The term “C₁₋₄ alkylthiocarboxamide” denotes a thioamide of thefollowing formulae:

wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₄ alkylthioureyl” denotes the group of the formula:—NC(S)N— wherein one are both of the nitrogens are substituted with thesame or different C₁₋₄ alkyl groups and alkyl has the same definition asdescribed herein. Examples of an alkylthioureyl include, but not limitedto, CH₃NHC(S)NH—, NH₂C(S)NCH₃—, (CH₃)₂N(S)NH—, (CH₃)₂N(S)NH—,(CH₃)₂N(S)NCH₃—, CH₃CH₂NHC(S)NH—, CH₃CH₂NHC(S)NCH₃—, and the like.

The term “C₁₋₄ alkylureyl” denotes the group of the formula: —NC(O)N—wherein one are both of the nitrogens are substituted with the same ordifferent C₁₋₄ alkyl group wherein alkyl has the same definition asdescribed herein. Examples of an alkylureyl include, but not limited to,CH₃NHC(O)NH—, NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NH—,(CH₃)₂N(O)NCH₃—, CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6 carbons andat least one carbon-carbon triple bond, some embodiments are 2 to 4carbons, some embodiments are 2 to 3 carbons, and some embodiments have2 carbons. Examples of an alkynyl include, but not limited to, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl and the like. The term “alkynyl” includes di- andtri-ynes.

The term “amino” denotes the group —NH₂.

The term “C₁₋₄ alkylamino” denotes one alkyl radical attached to anamino radical wherein the alkyl radical has the same meaning asdescribed herein. Some examples include, but not limited to,methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,sec-butylamino, iso-butylamino, t-butylamino, and the like. Someembodiments are “C₁₋₂ alkylamino.”

The term “aryl” denotes an aromatic ring radical containing 6 to 10 ringcarbons. Examples include phenyl and naphthyl.

The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—, —CH₂CH₂—and the like, which is further substituted with an aryl group. Examplesof an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to thenitrogen of an amide group, wherein aryl has the same definition asfound herein. The example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “carbo-C₁₋₆-alkoxy” refers to a C₁₋₆ alkyl ester of acarboxylic acid, wherein the alkyl group is as defined herein. In someembodiments, the carbo-C₁₋₆-alkoxy group is bonded to a nitrogen atomand together form a carbamate group (e.g., N—COO—C₁₋₆-alkyl). In someembodiments, the carbo-C₁₋₆-alkoxy group is an ester (e.g.,—COO—C₁₋₆-alkyl). Examples include, but not limited to, carbomethoxy,carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy,carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy,carbo-iso-pentoxy, carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy,and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “C₃₋₇ cycloalkenyl” denotes a non-aromatic ring radicalcontaining 3 to 6 ring carbons and at least one double bond; someembodiments contain 3 to 5 carbons; some embodiments contain 3 to 4carbons. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “C₃₋₇ cycloalkyl” denotes a saturated ring radical containing 3to 6 carbons; some embodiments contain 3 to 5 carbons; some embodimentscontain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.

The term “C₄₋₈ diacylamino” denotes an amino group bonded with two acylgroups defined herein wherein the acyl groups may be the same ordifferent, such as:

Examples of C₄₋₈ diacylamino groups include, but limited to,diacetylamino, dipropionylamino, acetylpropionylamino and the like.

The term “C₂₋₆ dialkylamino” denotes an amino substituted with two ofthe same or different alkyl radicals wherein alkyl radical has the samedefinition as described herein. Some examples include, but not limitedto, dimethylamino, methylethylamino, diethylamino, methylpropylamino,methylisopropylamino, ethylpropylamino, ethylisopropylamino,dipropylamino, propylisopropylamino and the like. Some embodiments are“C₂₋₄ dialkylamino.”

The term “C₁₋₄ dialkylcarboxamido” or “C₁₋₄ dialkylcarboxamide” denotestwo alkyl radicals, that are the same or different, attached to an amidegroup, wherein alkyl has the same definition as described herein. A C₁₋₄dialkylcarboxamido may be represented by the following groups:

wherein C₁₋₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but not limited to, N,N-dimethylcarboxamide,N-methyl-N-ethylcarboxamide, N,N-diethylcarboxamide,N-methyl-N-isopropylcarboxamide, and the like.

The term “C₂₋₆ dialkylsulfonamide” refers to one of the following groupsshown below:

wherein C₁₋₃ has the same definition as described herein, for examplebut not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

The term “C₂₋₆ dialkylthiocarboxamido” or “C₂₋₆ dialkylthiocarboxamide”denotes two alkyl radicals, that are the same or different, attached toa thioamide group, wherein alkyl has the same definition as describedherein. A C₁₋₄ dialkylthiocarboxamido may be represented by thefollowing groups:

Examples of a dialkylthiocarboxamide include, but not limited to,N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “C₂₋₆ dialkylsulfonylamino” refers to an amino group bondedwith two C₁₋₃ alkylsulfonyl groups as defined herein.

The term “ethynylene” refers to the carbon-carbon triple bond group asrepresented below:

The term “formyl” refers to the group —CHO.

The term “C₁₋₄ haloalkoxy” denotes a haloalkyl, as defined herein, whichis directly attached to an oxygen atom. Examples include, but notlimited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy and the like.

The term “C₁₋₄ haloalkyl” denotes an C₁₋₄ alkyl group, defined herein,wherein the alkyl is substituted with one halogen up to fullysubstituted and a fully substituted C₁₋₄ haloalkyl can be represented bythe formula C_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3 or4; when more than one halogen is present then they may be the same ordifferent and selected from the group consisting of F, Cl, Br and I,preferably F. Examples of C₁₋₄ haloalkyl groups include, but not limitedto, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “C₁₋₄ haloalkylcarboxamide” denotes an alkylcarboxamide group,defined herein, wherein the alkyl is substituted with one halogen up tofully substituted represented by the formula C_(n)L_(2n+1) wherein L isa halogen and “n” is 1, 2, 3 or 4. When more than one halogen is presentthey may be the same or different and selected from the group consistingof F, Cl, Br and I, preferably F.

The term “C₁₋₄ haloalkylsulfinyl” denotes a haloalkyl radical attachedto a sulfoxide group of the formula: —S(O)— wherein the haloalkylradical has the same definition as described herein. Examples include,but not limited to, trifluoromethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.

The term “C₁₋₄ haloalkylsulfonyl” denotes a haloalkyl radical attachedto a sulfone group of the formula: —S(O)₂— wherein haloalkyl has thesame definition as described herein. Examples include, but not limitedto, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2-difluoroethylsulfonyl and the like.

The term “C₁₋₄ haloalkylthio” denotes a haloalkyl radicaol directlyattached to a sulfur wherein the haloalkyl has the same meaning asdescribed herein. Examples include, but not limited to,trifluoromethylthio (i.e., CF₃S—), 1,1-difluoroethylthio,2,2,2-trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodogroup.

The term “C₁₋₂ heteroalkylene” refers to a C₁₋₂ alkylene bonded to aheteroatom selected from O, S, S(O), S(O)₂ and NH. Some representedexamples include, but not limited to, the groups of the followingformulae:

and the like.

The term “heteroaryl” denotes an aromatic ring system that may be asingle ring, two fused rings or three fused rings wherein at least onering carbon is replaced with a heteroatom selected from, but not limitedto, the group consisting of O, S and N wherein the N can be optionallysubstituted with H, C₁₋₄ acyl or C₁₋₄ alkyl. Examples of heteroarylgroups include, but not limited to, pyridyl, benzofuranyl, pyrazinyl,pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole,benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxalineand the like. In some embodiments, the heteroaryl atom is O, S, NH,examples include, but not limited to, pyrrole, indole, and the like.

The term “heterocyclic” denotes a non-aromatic carbon ring (i.e.,cycloalkyl or cycloalkenyl as defined herein) wherein one, two or threering carbons are replaced by a heteroatom selected from, but not limitedto, the group consisting of O, S, N, wherein the N can be optionallysubstituted with H, C₁₋₄ acyl or C₁₋₄ alkyl, and ring carbon atomsoptionally substituted with oxo or a thiooxo thus forming a carbonyl orthiocarbonyl group. The heterocyclic group is a 3-, 4-, 5-, 6- or7-membered containing ring. Examples of a heterocyclic group include butnot limited to aziridin-1-yl, aziridin-2-yl, azetidin-1-yl,azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4-yl,morpholin-4-yl, piperzin-1-yl, piperzin-4-yl, pyrrolidin-1-yl,pyrrolidin-3-yl, [1,3]-dioxolan-2-yl and the like.

The term “heterocyclic-carbonyl” denotes a heterocyclic group, asdefined herein, directly bonded to the carbon of a carbonyl group (i.e.,C═O). In some embodiments, a ring nitrogen of the heterocyclic group isbonded to the carbonyl group forming an amide. Examples include, but notlimited to,

and the like.

In some embodiments, a ring carbon is bonded to the carbonyl groupforming a ketone group.

Examples include, but not limited to,

and the like.

The term “heterocyclic-oxy” refers to a heterocyclic group, as definedherein, that is directly bonded to an oxygen atom. Examples include thefollowing:

and the like.

The term “heterocycliccarboxamido” denotes a heterocyclic group, asdefined herein, with a ring nitrogen where the ring nitrogen is bondeddirectly to the carbonyl forming an amide. Examples include, but notlimited to,

and the like.

The term “heterocyclicsulfonyl” denotes a heterocyclic group, as definedherein, with a ring nitrogen where the ring nitrogen is bonded directlyto an SO₂ group forming an sulfonamide. Examples include, but notlimited to,

and the like.

The term “hydroxyl” refers to the group —OH.

The term “hydroxylamino” refers to the group —NHOH.

The term “nitro” refers to the group —NO₂.

The term “C₄₋₇ oxo-cycloalkyl” refers to a C₄₋₇ cycloalkyl, as definedherein, wherein one of the ring carbons is replaced with a carbonyl.Examples of C₄₋₇ oxo-cycloalkyl include, but are not limited to,2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl,and the like and represented by the following structures respectively:

The term “perfluoroalkyl” denotes the group of the formula—C_(n)F_(2n+1); stated differently, a perfluoroalkyl is an alkyl asdefined herein wherein the alkyl is fully substituted with fluorineatoms and is therefore considered a subset of haloalkyl. Examples ofperfluoroalkyls include CF₃, CF₂CF₃, CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃,CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃ and the like.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term “phosphonooxy” refers to a group with the following chemicalstructure:

The term “sulfonamide” refers to the group —SO₂NH₂.

The term “sulfonic acid” refers to the group —SO₃H.

The term “tetrazolyl” refers to the five membered heteroaryl of thefollowing formulae:

In some embodiments, the tetrazolyl group is further substituted ateither the 1 or 5 position resepectively with a group selected from thegroup consisting of C₁₋₃ alkyl, C₁₋₃ haloalkyl and C₁₋₃ alkoxy.

The term “thiol” denotes the group —SH.

The term “GLP-1 secretagogue” shall mean an agent (e.g., a compound)that promotes GLP-1 secretion from a cell, e.g. an enteroendocrine cell.

The term “endogenous” shall mean a material that a mammal naturallyproduces.

The term “biologically active fragment of a G protein-coupled receptor”shall mean a fragment of the GPCR having structural and biochemicalfunctions of a naturally occurring GPCR. In certain embodiments, thebiologically active fragment couples to a G protein. In certainembodiments, the biologically active fragment binds to a known ligand ofthe GPCR.

The term “primer” is used herein to denote a specific oligonucleotidesequence which is complementary to a target nucleotide sequence and usedto hybridize to the target nucleotide sequence. A primer serves as aninitiation point for nucleotide polymerization catalyzed by DNApolymerase, RNA polymerase, or reverse transcriptase.

The term “expression vector” shall mean a DNA sequence that is requiredfor the transcription of cloned DNA and translation of the transcribedmRNA in an appropriate host cell recombinant for the expression vector.An appropriately constructed expression vector should contain an originof replication for autonomous replication in host cells, selectablemarkers, a limited number of useful restriction enzyme sites, apotential for high copy number, and active promoters. The cloned DNA tobe transcribed is operably linked to a constitutively or conditionallyactive promoter within the expression vector.

The term “candidate compound” or “test compound” shall mean a compound(for example and not limitation, a chemical compound) that is amenableto screening.

The term “contact” or “contacting” shall mean bringing at least twomoieties together.

The terms “modulate” or “modify” shall be taken to refer to an increaseor decrease in the amount, quality, or effect of a particular activity,function or molecule. By way of illustration and not limitation,agonists, partial agonists, inverse agonists, and antagonists of a Gprotein-coupled receptor are modulators of the receptor.

The term “small molecule” shall be taken to mean a compound having amolecular weight of less than about 10,000 grams per mole, including apeptide, peptidomimetic, amino acid, amino acid analogue,polynucleotide, polynucleotide analogue, nucleotide, nucleotideanalogue, organic compound or inorganic compound (i.e. including aheterorganic compound or organometallic compound), and salts, esters andother pharmaceutically acceptable forms thereof. In certain preferredembodiments, small molecules are organic or inorganic compounds having amolecular weight of less than about 5,000 grams per mole. In certainpreferred embodiments, small molecules are organic or inorganiccompounds having molecular weight of less than about 1,000 grams permole. In certain preferred embodiments, small molecules are organic orinorganic compounds having a molecular weight of less than about 800grams per mole. In certain preferred embodiments, small molecules areorganic or inorganic compounds having a molecular weight of less thanabout 600 grams per mole. In certain preferred embodiments, smallmolecules are organic or inorganic compounds having a molecular weightof less than about 500 grams per mole.

The term “polynucleotide” shall refer to RNA, DNA, or RNA/DNA hybridsequence of more than one nucleotide in either single chain or duplexform. The polynucleotides of the invention may be prepared by any knownmethod, including synthetic, recombinant, ex vivo generation, or acombination thereof, as well as utilizing any purification methods knownin the art.

The term “polypeptide” shall refer to a polymer of amino acids withoutregard to the length of the polymer. Thus, peptides, oligopeptides, andproteins are included within the definition of polypeptide. This termalso does not specify or exclude post-expression modifications ofpolypeptides. For example, polypeptides that include the covalentattachment of glycosyl groups, acetyl groups, phosphate groups, lipidgroups and the like are expressly encompassed by the term polypeptide.

The term “antibody” is intended herein to encompass monoclonal antibodyand polyclonal antibody.

The term “second messenger” shall mean an intracellular responseproduced as a result of receptor activation. A second messenger caninclude, for example, inositol 1,4,5-triphosphate (IP3), diacylglycerol(DAG), cyclic AMP (cAMP), cyclic GMP (cGMP), MAP kinase acitivity,MAPK/ERK kinase kinase-1 (MEKK1) activity, and Ca2+. Second messengerresponse can be measured for a determination of receptor activation.

The term “receptor functionality” shall refer to the normal operation ofa receptor to receive a stimulus and moderate an effect in the cell,including, but not limited to regulating gene transcription, regulatingthe influx or efflux of ions, effecting a catalytic reaction, and/ormodulating activity through G-proteins, such as eliciting a secondmessenger response.

The term “stimulate” or “stimulating,” in relationship to the term“response” or “functionality of the receptor” shall mean that a responseor a functionality of the receptor is increased in the presence of acompound as opposed to in the absence of the compound.

The term “inhibit” or “inhibiting,” in relationship to the term“response” or “functionality of the receptor” shall mean that a responsea functionality of the receptor is decreased or prevented in thepresence of a compound as opposed to in the absence of the compound.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the lower limit unless the contextclearly indicates otherwise, between the upper and lower limit of thatrange and any other stated or intervening value in that stated range, isencompassed within the invention. The upper and lower limits of thesesmaller ranges may independently be included in the smaller ranges, andare also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

GPR119 Agonists

Preferably, GPR119 is mammalian GPR119. More preferably, GPR119 isrodent or primate GPR119. Most preferably, GPR119 is human GPR119.

The class of GPR119 agonists useful in the novel therapeuticcombinations of the present invention include compounds which exhibit anacceptably high affinity for GPR119 receptor. The GPR119 agonist orpharmaceutically acceptable salt may be any agonist, more preferably aselective GPR119 agonist.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/001267 (published as WO 04/065380), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/001267 as a GPR119 agonist is acompound of Formula (I):

wherein:

-   -   A and B are independently C₁₋₃ alkylene optionally substituted        with 1 to 4 methyl groups;    -   D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;    -   V is selected from the group consisting of C₁₋₃ alkylene,        ethynylene and C₁₋₂ heteroalkylene wherein each are optionally        substituted with 1 to 4 substituents selected from the group        consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃        haloalkyl and halogen; or    -   V is absent;    -   W is NR₄, O, S, S(O) or S(O)₂; or    -   W is absent;    -   X is N or CR₅;    -   Y is N or CR₆;    -   Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₄₋₈        diacylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,        C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl,        heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro and        tetrazolyl, wherein C₁₋₈ alkyl and C₁₋₅ acyl are each optionally        substituted with 1, 2, 3 or 4 groups selected from the group        consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂        alkylamino, C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl,        C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, hydroxyl,        hydroxylamino and nitro; or    -   Z is a group of Formula (IA):        -   wherein:            -   R₇ is H, C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and            -   R₈ is H, nitro or nitrile;    -   Ar₁ is aryl or heteroaryl wherein each are optionally        substituted with R₉-R₁₃;    -   R₁ is selected from the group consisting of H, C₁₋₅ acyloxy,        C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,        C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄        alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano,        C₃₋cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio        and hydroxyl;    -   R₂ is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, hydroxyl and        phenyl; and wherein C₁₋₈ alkyl, heteroaryl and phenyl are each        optionally substituted with 1 to 5 substituents selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylene,        C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆        dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,        hydroxylamino and nitro; or    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are independently aryl or        heteroaryl each optionally substituted with 1 to 5 substituents        selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or    -   R₂ is a group of Formula (IB):        -   wherein:            -   R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl,                Br or CN; or    -   R₂ is a group of Formula (IC):        -   wherein:            -   G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇                are independently H or C₁₋₈ alkyl; and            -   Ar₄ is phenyl or heteroaryl optionally substituted with                1 to 5 substituents selected from the group consisting                of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,                C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄                alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄                alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄                alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,                carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆                dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆                dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄                haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄                haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio,                halogen, heteroaryl, hydroxyl, hydroxylamino and nitro;    -   R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy, halogen or hydroxyl;    -   R₄ is H or C₁₋₈ alkyl;    -   R₅ and R₆ are independently H, C₁₋₈ alkyl or halogen;    -   R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, arylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylamino, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic,        heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro, C₄₋₇        oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic acid,        and wherein C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl,        phenoxy and phenyl are each optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro        and phenyl; or    -   R₉ is a group of Formula (ID):        -   wherein:            -   “p” and “r” are independently 0, 1, 2 or 3; and            -   R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄                alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,                carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆                cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl                or phenyl, and wherein the heteroaryl and phenyl are                each optionally substituted with 1 to 5 substituents                selected independently from the group consisting of C₁₋₄                alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈                dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl                and hydroxyl; and    -   R₁₀—R₁₃ are independently selected form the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, hydroxyl and nitro; or    -   two adjacent R₁₀—R₁₁ groups together with Ar₁ form a 5, 6 or 7        membered cycloalkyl, cycloalkenyl or heterocyclic group wherein        the 5, 6 or 7 membered group is optionally substituted with        halogen.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/001267 include the following compoundsaccording to Formula (I) (referred to herein as Group A1):[6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1-yl}-aceticacid ethyl ester;(2-Fluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;{6-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;{6-[4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;4′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;{6-[4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;4′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;4′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;(4-Methoxy-2-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone;4-{4-[6-(4-Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[5-Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[6-(4-Butoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[6-(4-Isobutoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;{1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-fluoro-phenyl)-methanone;(2,3-Difluoro-phenyl)-{-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2,4-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-{2-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Acetyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;3′-Nitro-2′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylicacid ethyl ester;4-(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(2,4-Difluoro-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine;4-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidine;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-4-ylsulfanyl)-cyclohexyl]-pyrimidine;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl-cyclohexyl)-pyrimidine;1-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester; 1-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone;1-[6-(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine;{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(Morpholine-4-sulfonyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-Fluoro-phenyl)-{1-[5-nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-methanone;[5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;2-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1yl}-pyrimidin-4-yl)-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(6-{4-[5-(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-pyridin-2-ylmethyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;1-{6-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Benzoyl-5-methoxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;3′-Nitro-4′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester; 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(4,5-Dichloro-imidazol-1-yl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;Benzo[1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone;(2,5-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbonitrile;5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbaldehyde;5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carbaldehyde;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylicacid;[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-yl]-methanol;[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)-pyrimidine-5-carbonitrile;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile;1-{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one;1-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one;{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;[6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amineand5-Nitro-4-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/005555 (published as WO 04/076413), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/005555 as a GPR119 agonist is acompound of Formula (II):

wherein:

-   -   A and B are independently C₁₋₃ alkylene optionally substituted        with 1 to 4 methyl groups;    -   U is N or CR₁;    -   D is O, S, S(O), S(O)₂, CR₂R₃ or NR₂;    -   V is selected from the group consisting of C₁₋₃ alkylene,        ethynylene and C₁₋₂ heteroalkylene optionally substituted with 1        to 4 substituents selected from the group consisting of C₁₋₃        alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;        or V is absent;    -   W is —S(O)₂NR₄—, —NR₄—, —O—, —S—, —S(O)—, —S(O)₂—; or W is        absent;    -   X is N or CR₅;    -   Y is N or CR₆;    -   Z is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₄₋₈ diacylamino, C₁₋₄ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,        C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl,        heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl; or    -   Z is a group of Formula (IIA):        -   wherein:            -   R₇ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and            -   R₈ is H, nitro or cyano;    -   Ar₁ is aryl or heteroaryl optionally substituted with R₉, R₁₀,        R₁₁, R₁₂ and R₁₃;    -   R₁, R₅ and R₆ are independently selected from the group        consisting of H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈        dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl and nitro;    -   R₂ is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, hydroxyl and        phenyl; and wherein C₁₋₈ alkyl, heteroaryl and phenyl are        optionally substituted with 1 to 5 substituents selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino        and nitro; or    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are independently aryl or        heteroaryl optionally substituted with 1 to 5 substituents        selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or    -   R₂ is a group of Formula (IIB):        -   wherein:            -   R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl,                Br or CN; or    -   R₂ is a group of Formula (IIC):        -   wherein:            -   G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇                are independently H or C₁₋₈ alkyl; and            -   Ar₄ is phenyl or heteroaryl optionally substituted with                1 to 5 substituents selected from the group consisting                of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,                C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄                alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄                alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄                alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,                carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆                dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆                dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄                haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄                haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio,                halogen, heteroaryl, hydroxyl, hydroxylamino and nitro;    -   R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy or hydroxyl;    -   R₄ is H or C₁₋₈ alkyl;    -   R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, arylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro,        C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic        acid, and wherein C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl,        phenoxy and phenyl are optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro        and phenyl; or    -   R₉ is a group of Formula (IID):        -   wherein:            -   “p” and “r” are independently 0, 1, 2 or 3; and            -   R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄                alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,                carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆                cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl                or phenyl, and wherein the heteroaryl or phenyl                optionally substituted with 1 to 5 substituents selected                independently from the group consisting of C₁₋₄ alkoxy,                C₁₋₈ alkyl, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈                dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl                and hydroxyl; and    -   R₁₀—R₁₃ are independently selected form the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl and nitro; or    -   two adjacent R₁₀—R₁₁ groups form a 5, 6 or 7 membered        cycloalkyl, cycloalkenyl or heterocyclic group with Ar₁ wherein        the 5, 6 or 7 membered group is optionally substituted with        halogen.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B 1):6′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;1-[4-(4-Acetyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-ethanone;6′-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-[4-(2-Methoxy-ethyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Cyclopentyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4′-Cyano-biphenyl-4-yloxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-sulfo-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-pyrrol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Carbamoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-[4-(4-oxo-cyclohexyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4′-Methoxy-biphenyl-4-yloxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-3-oxo-propionicacid methyl ester;4-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-butan-2-one;4-{4-[3′-Nitro-4-(pyridin-2-ylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy]-phenyl}-butan-2-one;and3′-Nitro-4-(pyridin-2-ylsulfanyl)-6′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B2):1-[5-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acidethyl ester;1-{5-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-2-nitro-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-[5-(2-Amino-4-ethanesulfonyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylicacid ethyl ester;1-{2-Nitro-5-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester;4-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone;3-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionicacid methyl ester;5-Ethanesulfonyl-2-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenylamine;{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone;1-{4-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester;4-{4-[2-Nitro-5-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one;1-[3-(4-Benzoyl-phenoxy)-4-nitro-phenyl]-piperidine-4-carboxylic acidethyl ester;{4-[2-Nitro-5-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone;1-{5-[4-(2-Carboxy-ethyl)-phenoxy]-2-nitro-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-{5-[4-(2-Carboxy-2-oxo-ethyl)-phenoxy]-2-nitro-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-[2-Nitro-5-(4-vinyl-phenoxy)-phenyl]-piperidine-4-carboxylic acidethyl ester;3-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-propionicacid;3-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-2-oxo-propionicacid; 1-[2-Nitro-5-(4-vinyl-phenoxy)-phenyl]-4-propyl-piperidine;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-1-one;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-pentan-1-one;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-hexan-1-one;4-{4-[3-(4-Methoxymethyl-piperidin-1-yl)-4-nitro-phenoxy]-phenyl}-butan-2-one;1-{4-[3-(4-Methoxymethyl-piperidin-1-yl)-4-nitro-phenoxy]-phenyl}-ethanone;{4-[3-(4-Methoxymethyl-piperidin-1-yl)-4-nitro-phenoxy]-phenyl}-phenyl-methanone;2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-{4-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone;4-(4-{3-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-4-nitro-phenoxy}-phenyl)-butan-2-one;4-(4-{4-Nitro-3-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-phenoxy}-phenyl)-butan-2-one;2-{1-[2-Nitro-5-(4-[1,2,4]triazol-1-yl-phenoxy)-phenyl]-piperidin-4-ylsulfanyl}-pyridine;2-Methyl-5-{4-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-2H-pyrazol-3-ol;2-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-5-trifluoromethyl-pyridine;5-Bromo-2-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-pyridine;1-(4-{4-Nitro-3-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-phenoxy}-phenyl)-ethanone;2-{1-[5-(4-Methanesulfonyl-phenoxy)-2-nitro-phenyl]-piperidin-4-ylsulfanyl}-pyridine;1-{5-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-2-nitro-phenyl}-4-propyl-piperidine;1-{5-[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenoxy]-2-nitro-phenyl}-4-propyl-piperidine.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundaccording to Formula (II) (referred to herein as Group B3):5-Bromo-1-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenyl]-1H-pyridin-2-one.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B4):6′-Benzenesulfonylamino-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(Benzenesulfonyl-methyl-amino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(Benzenesulfonyl-butyl-amino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(5-Ethanesulfonyl-2-hydroxy-phenylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(2-Bromo-4-trifluoromethyl-benzenesulfonylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-1,2′]bipyridinyl-4-carboxylicacid ethyl ester;{4-[3′-Nitro-4-(pyridin-2-ylsulfanyl)-3,4,5,6-tetrahydro-2H-1,2′]bipyridinyl-6′-ylamino]-phenyl}-phenyl-methanoneand[3′-Nitro-4-(pyridin-2-ylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B5):1-[5-(4-Benzoyl-phenylamino)-2-nitro-phenyl]-piperidine-4-carboxylicacid ethyl ester and{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenylamino]-phenyl}-phenyl-methanone.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/022327 (published as WO 05/007647), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/022327 as a GPR119 agonist is acompound of Formula (III):

-   -   wherein:    -   A and B are each independently C₁₋₃ alkylene optionally        substituted with 1 to 4 substituents selected from the group        consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃        haloalkyl and halogen;    -   D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;    -   E is N, C or CR₄;    -   is a single bond when E is N or CR₄, or a double bond when E is        C;    -   V₁ is selected from the group consisting of C₁₋₃ alkylene,        ethynylene and C₁₋₂ heteroalkylene optionally substituted with 1        to 4 substituents selected from the group consisting of C₁₋₃        alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;        or V₁ is a bond;    -   V₂ is C₃₋₆ cycloalkylene or C₁₋₃ alkylene wherein each are        optionally substituted with 1 to 4 substituents selected from        the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano,        C₁₋₃ haloalkyl and halogen; or V₂ is a bond;    -   W is NR₅, O, S, S(O) or S(O)₂; or W is absent;    -   Q is NR₆, O, S, S(O) or S(O)₂;    -   X is N or CR₇;    -   Y is N or CR₈;    -   Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylthiocarboxamide, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂        alkylamino, C₂₋₄ dialkylamino, carbamimidoyl, carbo-C₁₋₆-alkoxy,        carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈ diacylamino,        C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        halogen, aryl, heterocyclic, heteroaryl, hydroxyl,        hydroxycarbamimidoyl, hydroxylamino, nitro and tetrazolyl,        wherein C₁₋₈ alkyl, C₃₋₇ cycloalkyl, and heterocyclic are each        optionally substituted with 1, 2, 3 or 4 groups selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, formyl, C₁₋₄        haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro, and        wherein said C₁₋₇ alkyl is optionally substituted with amino; or    -   Z is a group of Formula (IIIA):    -   wherein:    -   R₉ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and    -   R₁₀ is H, nitro or nitrile;    -   Ar₁ is aryl or heteroaryl each optionally substituted with R₁₁,        R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group        consisting of C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy,        C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,        heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,        heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl,        phenoxy, phenyl, sulfonamide, sulfonic acid, and thiol, and        wherein C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆        dialkylamino, heterocyclic, heterocyclic-carbonyl, heteroaryl,        phenoxy and phenyl are optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl,        C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro,        phenyl, and phosphonooxy, wherein said C₁₋₇ alkyl and C₁₋₄        alkylcarboxamide are each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₄ alkoxy        and hydroxy; or    -   R₁₁ is a group of Formula (IIIB):    -   wherein:    -   “p” and “r” are each independently 0, 1, 2 or 3; and R₁₆ is H,        C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆        alkynyl, C₁₋₄ alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, heteroaryl or phenyl, and wherein the heteroaryl or        phenyl optionally substituted with 1 to 5 substituents selected        independently from the group consisting Of C₁₋₄ alkoxy, amino,        C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl and hydroxyl; and    -   R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the        group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄        alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        hydroxyl and nitro; or    -   two adjacent groups selected from the group consisting of R₁₂,        R₁₃, R₁₄ and R₁₅ together with the atoms to which they are        attached form a 5-, 6- or 7-membered cycloalkyl, cycloalkenyl or        heterocyclic group fused with Ar₁, wherein the 5-, 6- or        7-membered group is optionally substituted with halogen;    -   R₁, R₇ and R₈ are each independently selected from the group        consisting of H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈        dialkylamino, carboxamide, cyano, C₃₋₇ cycloalkyl, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio and hydroxyl;    -   R₂ is selected from the group consisting of C₁₋₈ alkyl, amino,        aryl, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl and hydroxyl;        and wherein C₁₋₈ alkyl, aryl or heteroaryl optionally        substituted with 1 to 5 substituents selected from the group        consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino        and nitro; or    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl        or heteroaryl optionally substituted with 1 to 5 substituents        selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxanide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, C₁₋₄ alkylamino, carbo-C₁₋₆-alkoxy,        carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino,        C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,        halogen, hydroxyl and nitro; or    -   R₂ is a group of Formula (IIIC):    -   wherein:    -   R₁₇ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl or OR₁₉;        and R₁₈ is F, Cl, Br, CN or NR₂₀R₂₁; where R₁₉ is H, C₁₋₈ alkyl        or C₃₋₇ cycloalkyl, and R₂₀ and R₂₁ are each independently H,        C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl or heteroaryl; or    -   R₂ is a group of Formula (IIID):    -   wherein:    -   G is:    -   i) —C(O)—, —C(O)NR₂₃—, —C(O)O—, —OC(O)NR₂₃—, —NR₂₃C(O)O—,        —OC(O)—, —C(S)—, —C(S)NR₂₃—, —C(S)O—, —OC(S)—, —CR₂₃R₂₄—, —O—,        —S—, —S(O)— or —S(O)₂— when D is CR₂R₃, or    -   ii) —CR₂₃R₂₄C(O)—, —C(O)—, —CR₂₃R₂₄C(O)NR₂₅—, —C(O)NR₂₃—,        —C(O)O—, —C(S)—, —C(S)NR₂₃—, —C(S)O—, —CR₂₃R₂₄—, —S(O)₂—, or a        bond when D is NR₂,    -   wherein R₂₃, R₂₄ and R₂₅ are each independently H or C₁₋₈ alkyl;        and R₂₂ is H, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl,        heteroaryl, or heterocyclic each optionally substituted with 1        to 5 substituents selected from the group consisting of C₁₋₅        acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄        alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heteroaryl, heterocyclic, hydroxyl,        hydroxylamino, nitro, phenyl, phenoxy, and sulfonic acid,        wherein said C₁₋₇ alkyl, heteroaryl, phenyl and phenoxy are each        optionally substituted with 1 to 5 substituents selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,        hydroxylamino, and nitro;    -   R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy or hydroxyl; and    -   R₄, R₅ and R₆ are each independently H, C₁₋₈ alkyl or C₃₋₇        cycloalkyl, wherein said C₁₋₈ alkyl is optionally substituted        with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C1):3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;4-[5-cyano-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;[6-(1-Hexyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;[6-(1-Cyclopropylmethyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-isopropyl-5-methyl-cyclohexyl ester;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;(2-Chloro-pyridin-3-yl)-{4-[6-(4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl-methanone;(4-Methanesulfonyl-phenyl)-[6-(1-methanesulfonyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(propane-1-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;{6-[1-(Butane-1-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(thiophene-2-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine;{6-[1-(2,4-Dimethyl-thiazole-5-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-[5-Cyano-6-(3-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methanesulfonyl-pyridin-3-ylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;4-(4-Methanesulfonyl-phenylamino)-6-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;4-[1-(3,3-Dimethyl-2-oxo-butyl)-piperidin-4-yloxy]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile;4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-3-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;4-(1-Formyl-piperidin-4-yloxy)-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrileand4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C2):4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-1-one;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-2-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-amine;{6-[1-(3,3-Dimethyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;{6-[1-(2-Ethoxy-ethyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester;4-{2-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester;3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester and3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C3):4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;N-(4-Methanesulfonyl-phenyl)-5-nitro-N′-piperidin-4-yl-pyrimidine-4,6-diamine;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-ethanoneand1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-2,2-dimethyl-propan-1-one.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C4):4-[6-(4-Cyano-2-fluoro-phenylamino)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamino}-3-fluoro-benzonitrile;{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;4-{6-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-sulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Fluoro-ethyl)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[4-Fluoro-6-(2-isopropoxy-ethyl)-pyridin-3-ylamino]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-[1,2,4]triazol-1-yl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[2-fluoro-4-(4-methoxy-pyridin-2-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-propionylsulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{6-[2,3-Difluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C5):4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;1-[4-(1-Benzyl-azetidin-3-yloxy)-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone;4-[5-Cyano-6-(6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(6-propyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethylsulfanyl)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethanesulfonyl)-2-fluoro-phenylamino]-3-oxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(3-methyl-butylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethylamino)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(4-dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(2-pyrrolidin-1-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propylamino-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methoxy-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(2-methanesulfonyl-ethyl)-methyl-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(2-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-(4,5-Dihydro-1H-imidazol-2-yl)-6-(2-fluoro4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidin-4-yl}-amine;4-[6-(2-Fluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Carbamimidoyl-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(4-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethoxy)-4-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylsulfamoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[(2-Fluoro-4-methanesulfonyl-phenyl)-(2-methoxy-ethyl)-amino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamimidoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;4-{6-[2-Fluoro-4-(pyridin-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-methyl-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-4-fluoro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundaccording to Formula (III) (referred to herein as Group C6):4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C7):4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-methoxy-propyl)-piperidin-4-yloxy]-5-methyl-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-2-ol;4-{6-[2-Fluoro-4-(5-isopropoxymethyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(5-methoxy-pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Cyclopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(pyridine-2-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methanesulfonylamino-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methoxy-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-propan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-ethanone;N-(4-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;N-(3-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;N-(3,5-Dichloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-trifluoromethyl-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-phenyl-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-isopropyl-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-methoxy-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(3-trifluoromethyl-phenyl)-acetamide;4-{6-[2-Fluoro-4-(3-methoxy-propane-1-sulfonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methyl-6-[2-methyl-6-(2-pyridin-2-yl-ethoxy)-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(thiophene-2-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{6-[(2-Isopropoxy-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Amino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-pyrimidine;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-morpholin-4-yl-ethanone;1-(3,4-Dichloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(3-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-3-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-phenyl-ethanone;1-(2,4-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(4-methyl-pentyl)-piperidin-4-yloxy]-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-isopropoxy-propan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-isopropoxy-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-propan-1-one;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(5-pyridin-2-yl-thiophen-2-yl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(5-methyl-hexyl)-piperidin-4-yloxy]-pyrimidine;3-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-oxo-propane-1-sulfonicacid;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(1-pentyl-piperidin-4-yloxy)-pyrimidine;4-(1-Butyl-piperidin-4-yloxy)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-cyclohexanecarboxylicacid;1-(4-Diethylamino-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(2-methyl-4-phenyl-furan-3-yl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-(1-hexyl-piperidin-4-yloxy)-5-methyl-pyrimidine;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butyricacid;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-6-methyl-heptan-2-one;5-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-pentanoicacid;5-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-pentanenitrile;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-pyridin-2-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-4-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-ylmethyl}-acrylicacid;1-[1,4]Dioxan-2-yl-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(2,3-Dihydro-[1,4]dioxin-2-yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-p-tolyl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-methoxy-phenyl-ethanone;1-(2-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;3-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetyl)-benzonitrile;1-(2,4-Dimethyl-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Chloro-3-methyl-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Difluoromethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(5-phenyl-thiophen-2-yl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-aceticacid ethyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-2-ol;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(4-methoxy-cyclohexyl)-piperidin-4-yloxy]-5-methyl-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-1-one;4-{6-[2-Fluoro-4-(2-isobutoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Cyclopropoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(3-methoxy-propoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-pyridin-2-yl-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-tert-Butoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-sulfo-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-trifluoromethoxy-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-trifluoromethoxy-phenoxy)-5-prop-1-ynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-methoxy-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(6-methoxy-4-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[6-(2-isopropoxy-ethyl)-2-methyl-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-4-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidin-1-yl}-3-pyridin-2-yl-propan-1-one;4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yloxy}-3-fluoro-benzonitrile;5-Ethynyl-4-(2-fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidine;4-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidine;4-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidine;4-[6-(2-Fluoro-4-methanesulfonylamino-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;cis-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid isopropyl ester;trans-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid isopropyl ester;N-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-3-methyl-butyramide;N-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-isobutyramide;4-{6-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-Fluoro-6-(2-methanesulfonyl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyclopropyl-6-[2,5-difluoro-4-(2-hydroxy-ethyl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(5-Cyclopropyl-6-{2,5-difluoro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Fluoro-ethyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(1-hydroxy-cyclopropylmethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(R)-4-(6-{2-Fluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(S)-4-(6-{2-Fluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(R)-4-(5-Ethynyl-6-{2-fluoro-4-[2-(2-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(S)-4-(2-{2-Fluoro-4-[2-(2-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-Fluoro-6-(2-morpholin-4-yl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[4-fluoro-6-(2-methanesulfonyl-ethyl)-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2,5-Difluoro-4-(2-isopropoxy-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-propionylsulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-sulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-sulfamoyl-ethyl)-phenoxy]-5-ethynyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,3-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-{2-Fluoro-4-[2-(6-methoxy-pyridin-2-yl)-ethyl]-phenoxy}-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(3-methoxy-pyridin-2-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Fluoro-1-oxy-pyridin-4-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5′-Methoxy-6-methyl-[2,2′]bipyridinyl-5-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[2-fluoro-4-(4-methoxy-pyridin-2-yl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(3-methoxy-pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2,5-Difluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester; and4-(6-{2,5-Difluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-ethynyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C8):4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-methanone;(6-Amino-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[5-Ethyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(2-methyl-6-pentyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(2-pyridin-3-yl-ethyl)-piperidin-4-yloxy]-pyrimidine;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;4-{6-[6-(2-Methoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine;4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Iodo-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[N-(2-isopropoxy-ethyl)-carbamimidoyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(4-Bromo-2-fluoro-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine;4-[6-(5-Methanesulfonyl-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyclopropyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-butyricacid;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone;4-{6-[6-(2-Methoxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-(2,5-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;4-[6-(6-Chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-fluoro-phenyl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethyl-phenyl)-ethanone;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-3-yl-ethanone;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-2-one;4-(6-{2-Fluoro-4-[(2-isopropoxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-methanesulfonyl-phenyl)-ethanone;1-(4-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetyl)-benzonitrile;1-(3,4-Difluoro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one;4-[6-(2,4-Difluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-1-one;4-{6-[2-Fluoro-4-(2-methoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(methoxy-methyl-carbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-1-one;4-[6-(4-Cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-(5-Aminomethyl-4,5-dihydro-oxazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Benzylamino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylamino)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(6-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-hydroxycarbamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(4-isopropyl-piperazine-1-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Dimethylcarbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propionylsulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-phosphonooxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Bromo-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(2-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-{[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl}-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-3-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;C-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-C-(4-fluoro-phenyl)-methyleneamine;3-tert-Butoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-propan-1-one;2-Ethoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-(tetrahydro-furan-2-yl)-methanone;(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one;4-(6-{2-Fluoro-4-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-imidazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(R)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one;(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-butan-1-one;(R)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide;(S)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide;(R)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide;(S)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (S)-tetrahydro-furan-3-yl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (R)-tetrahydro-furan-3-yl ester;4-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester;4-{6-[2-Fluoro-4-(6-methoxy-pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;3-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one;2-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-[5-Methyl-6-(4-sulfo-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C9):4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester; and4-({Cyclopropylmethyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundaccording to Formula (III) (referred to herein as Group C10):4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/022417 (published as WO 05/007658), the disclosure ofeach of which is herein incorporated by reference in its entirety.Disclosed in International Application No. PCT/US2004/022417 as a GPR119agonist is a compound of Formula (IV):

-   -   wherein:    -   A and B are each independently C₁₋₃ alkylene optionally        substituted with 1 to 4 substituents selected from the group        consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃        haloalkyl and halogen;    -   D is O, S, S(O), S(O)₂, CR₁R₂ or N—R₂, wherein R₁ is selected        from the group consisting of H, C₁₋₈ alkyl, C₁₋₄ alkoxy, halogen        and hydroxyl;    -   E is N, C or CR₃, wherein R₃ is H or C₁₋₈ alkyl;    -   is a single bond when E is N or CR₃, or a double bond when E is        C;    -   K is a C₃₋₆ cycloalkylene or C₁₋₃ alkylene wherein each are        optionally substituted with 1 to 4 substituents selected from        the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano,        C₁₋₃ haloalkyl and halogen; or K is a bond;    -   Q is NR₄, O, S, S(O) or S(O)₂, wherein R₄ is H or C₁₋₈ alkyl and        the C₁₋₈ alkyl is optionally substituted with C₂₋₈ dialkylamine;    -   T is N or CR₅;    -   M is N or CR₆;    -   J is N or CR₇;    -   U is C or N;    -   V is N, CR₈ or V is a bond;    -   W is N or C;    -   X is O, S, N, CR₉ or NR₁₁;    -   Y is O, S, N, CR₁₀ or NR₁₂;    -   Z is C or N;    -   R₅, R₆, R₇, R₈, R₉ and R₁₀ are each independently selected from        the group consisting of H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄        alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈        dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, hydroxylamino        and nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆ alkynyl        and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4        substituents selected from the group consisting of C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈        dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro;    -   R₁₁ and R₁₂ are each independently selected from C₂₋₆ alkenyl,        C₁₋₈ alkyl, C₂₋₆alkynyl or C₃₋₆ cycloalkyl each optionally        substituted with 1, 2, 3 or 4 substituents selected from the        group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄        alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈        dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro;    -   Ar₁ is aryl or heteroaryl each optionally substituted with R₁₃,        R₁₄, R₁₅, R₁₆, and R₁₇; wherein R₁₃ is selected from the group        consisting of C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy,        C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,        heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,        heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl,        phenoxy, phenyl, sulfonamide, sulfonic acid, and thiol, and        wherein said C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆        dialkylamino, heterocyclic, heterocyclic-carbonyl, heteroaryl,        phenoxy and phenyl are optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl,        C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro,        phenyl, and phosphonooxy, and wherein said C₁₋₇ alkyl and C₁₋₄        alkylcarboxamide are each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₄ alkoxy        and hydroxy; or    -   R₁₃ is a group of Formula (IVA):        -   wherein:            -   “p” and “r” are independently 0, 1, 2 or 3; and            -   R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄                alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,                carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇                cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl                or phenyl, and wherein said heteroaryl or phenyl                optionally substituted with 1 to 5 substituents selected                independently from the group consisting of C₁₋₄ alkoxy,                amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,                halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl;    -   R₁₄, R₁₅, R₁₆, and R₁₇ are each independently selected form the        group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl,        C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆-dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        hydroxyl and nitro; or    -   two adjacent R₁₄, R₁₅, R₁₆ and R₁₇ together with the atoms to        which they are attached form a 5, 6 or 7 member cycloalkyl,        cycloalkenyl or heterocyclic group fused with Ar₁ wherein the 5,        6 or 7 member group is optionally substituted with halogen; and    -   R₂ is selected from the group consisting of C₁₋₈ alkyl, C₂₋₆        alkynyl, amino, aryl, carboxamide, carboxy, cyano,        C₃₋₆-cycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,        heteroaryl and hydroxyl; and wherein said C₁₋₈ alkyl, aryl and        heteroaryl are each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonanide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,        hydroxylamino and nitro; or    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl        or heteroaryl each optionally substituted with 1 to 5        substituents selected from the group consisting of H, C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,        C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, amino, C₁₋₄ alkylamino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or    -   R₂ is a group of Formula (IVB):        -   wherein:            -   R₁₉ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl                or OR₂₁; and R₂₀ is F, Cl, Br, CN or NR₂₂R₂₃; where R₂₁                is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, and R₂₂ and R₂₃ are                independently H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl or                heteroaryl;

or

-   -   R₂ is a group of Formula (IVC):    -   wherein:    -   G is:    -   i) —C(O)—, —C(O)NR₂₅—, —NR₂₅C(O)—, —NR₂₅—, —NR₂₅C(O)O—,        —OC(O)NR₂₅—, —CR₂₅R₂₆NR₂₇C(O)—, —CR₂₅R₂₆C(O)NR₂₇—, —C(O)O—,        —OC(O)—, —C(S)—, —C(S)NR₂₅—, —C(S)O—, —OC(S)—, —CR₂₅R₂₆—, —O—,        —S—, —S(O)—, —S(O)₂— or a bond when D is CR₂R₃; or    -   ii) —CR₂₅R₂₆C(O)—, —C(O)—, —CR₂₅R₂₆C(O)NR₂₇—, —C(O)NR₂₅—,        —C(O)O—, —C(S)—, —C(S)NR₂₅—, —C(S)O—, —CR₂₅R₂₆—, —S(O)₂—, or a        bond when D is NR₂;    -   wherein R₂₅, R₂₆ and R₂₇ are each independently H or C₁₋₈ alkyl;        and R₂₄ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl,        or heterocyclic each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₅ acyl,        C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄        alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heteroaryl, heterocyclic, hydroxyl,        hydroxylamino, nitro, phenyl, phenoxy, and sulfonic acid,        wherein said C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino,        heteroaryl, phenyl and phenoxy are each optionally substituted        with 1 to 5 substituents selected from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino,        nitro, and phenyl;    -   provided that Z and U are not both N.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D1):4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;(3-Fluoro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid isobutyl ester;Furan-2-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(1-methyl-1H-pyrrol-2-yl)-methanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-3-yl-ethanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(2-methyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-isoxazol-3-yl)-methanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyrazin-2-yl-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-pyrazin-2-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyrimidin-5-yl-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyridazin-4-yl-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-thiophen-2-yl-methanone;(3,4-Dimethyl-isoxazol-5-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;3-tert-Butoxy-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-propan-1-one;(3-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-3-oxo-propyl)-methyl-carbamicacid tert-butyl ester;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-trifluoromethyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane-1,4-diamine;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-methyl-[1,2,3]thiadiazol-5-yl)-methanone;(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(2,5-Dimethyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(3-methyl-isoxazol-5-yl)-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbothioicacid pyridin-4-ylamide;N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-nicotinamide;3-tert-Butoxy-N-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-propionamide;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[1-(3,5-Bis-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-azetidine-1-carboxylicacid isopropyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid propyl ester;4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;{4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;{4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane-1,4-diamine;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(2-methyl-pyridin-3-yl)-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-pyridin-3-yl-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(1-methyl-1H-pyrrol-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid tert-butyl ester;N-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane-1,4-diamine;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-trifluoromethyl-pyridin-3-yl)-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclohexyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-pyran-4-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclopentyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-furan-3-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-furan-3-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-thiopyran-4-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclobutyl ester;(6-tert-Butyl-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamicacid tert-butyl ester;N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexylmethyl}-nicotinamide;N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexylmethyl}-6-methyl-nicotinamide;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-({[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester;3-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-{1-[2-(2-Dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid tert-butyl ester;3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid pyridin-3-ylmethyl esteracid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-pyridin-3-yl-ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 3-pyridin-3-yl-propyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-dimethylamino-ethyl ester;4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[6-Dimethylamino-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;1-(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-piperidin-1-yl)-3,3-dimethyl-butan-2-one;4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-piperidine-1-carboxylicacid cyclobutyl ester; and4-[({1-[4-(2-Methanesulfonyl-ethyl)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D2):4-({[1-(2,5-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone;2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone;2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;(2,5-Dimethyl-furan-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-({(2-Dimethylamino-ethyl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({(2-Dimethylamino-ethyl)-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-(2-{Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-ethyl)-piperazine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester;4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-ethyl}-piperazine-1-carboxylicacid ethyl ester;4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-propyl}-piperazine-1-carboxylicacid ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfinyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfonyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 2-methoxy-ethyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 3,3-dimethyl-butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 4-methyl-pentyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid cyclopropylmethyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid cyclobutylmethyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 2-cyclopropyl-ethyl ester;(5-Bromo-furan-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-morpholin-4-ylmethyl-furan-2-yl)-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid pentyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 1-ethyl-propyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-ethyl-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclopentylmethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-pyrrolidin-1-yl-ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-morpholin-4-yl-ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2,2-dimethyl-propyl ester;(5-Butyl-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-amine;Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-amine;[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;5′-Fluoro-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine;[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine;(4-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;(5′-Fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;-4-yl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;(5-Bromo-pyridin-3-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester;3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid isopropyl ester;(6-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanone;(2-Chloro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Hydroxy-3-methoxy-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Chloro-3-nitro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-pyrazol-1-yl-pyridin-3-yl)-methanone;(2-Hydroxy-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5,6-Dichloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Bromo-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-nicotinicacid;(1H-Imidazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-pyrrolidin-1-yl-pyridin-3-yl)-methanone;(6-Isobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Ethylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Cyclobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Isopropylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;[6-(1-Ethyl-propylamino)-pyridin-3-yl]-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(1-propyl-butylamino)-pyridin-3-yl]-methanone;5-Benzyloxy-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-pyran-4-one;Benzo[c]isoxazol-3-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Iodo-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-butan-2-one;2-(5-Bromo-pyridin-3-yl)-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin4-yloxy]-piperidin-1-yl}-ethanone;(6-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Fluoro-pyridin-2-y)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(2-Chloro-5-fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-[5-(2-methyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-methyl-pyridin-2-yl)-methanone;5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-nicotinonitrile;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-methoxy-pyridin-2-yl)-methanone;(2-Fluoro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(2-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-methoxy-thiophen-3-yl)-methanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-pyran-4-one;(5-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Ethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-pyridin-2-yl-thiophen-2-yl)-methanone;(5-Amino-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Amino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-[5-(3-methyl-butylamino)-pyridin-2-yl]-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-trifluoromethoxy-phenyl)-methanone;(5-Butyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Ethylamino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-isopropoxymethyl-pyridin-2-yl)-methanone;(4-Difluoromethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-isopropoxy-pyridin-2-yl)-methanone;5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-pyridine-2-carboxylicacid methyl ester;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-aceticacid ethyl ester;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(3-trifluoromethoxy-phenyl)-methanone;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Chloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5′-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;1-(4-Methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Chloro-3-methyl-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(3,4-Dichloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;5′-Bromo-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-trifluoromethoxy-phenyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;1-(2,4-Dimethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Difluoromethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Diethylamino-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;(2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-pyrimidin-4-yl)-dimethyl-amine;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(5-methyl-4-pyrrolidin-1-yl-pyrimidin-2-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Methyl-4-propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Isopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Methyl-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{1-[4-(2-Methoxy-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Bromo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-2-methyl-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(1-{2-Methyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Cyclopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{1-[4-(2-Dimethylamino-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Fluoro-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{1-[4-(2-Methoxy-ethylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[(Tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-ylsulfanyl]-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(2-Fluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Cyano-2-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-(2,5-Difluoro-4-methoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Fluoro-6-methoxy-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(6-Methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2,5-Difluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-hydroxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-(6-methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-(6-methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;4-[1-(2-Fluoro-4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Difluoromethoxy-2-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2,5-Difluoro-4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-phenol;1-(2-Fluoro-4-methoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Difluoromethoxy-2-fluoro-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2-Fluoro-4-trifluoromethoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2,5-Difluoro-4-methoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-phenol;1-(2-Fluoro-4-methoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Difluoromethoxy-2-fluoro-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;and1-(2-Fluoro-4-trifluoromethoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D3):4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isobutyl ester;{4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;4-[9-(4-Methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid tert-butyl ester and4-[9-(2-Fluoro-4-methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D4):4-[9-(2-Fluoro-4-propionylsulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(4-Cyano-2-fluoro-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(2-Fluoro-4-sulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;9-(2-Fluoro-4-methanesulfonyl-phenyl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9H-purine;3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-benzonitrile;3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-benzenesulfonamide;4-[9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(4-Fluoro-6-methoxy-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(6-Methoxy-2-methyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(2,5-Difluoro-4-sulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9H-purine;9-(4-Fluoro-6-methoxy-pyridin-3-yl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9H-purine;6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9-(6-methoxy-2-methyl-pyridin-3-yl)-9H-purine;2,5-Difluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-benzenesulfonamide;9-(2-Fluoro-4-methanesulfonyl-phenyl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9H-purine;3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-benzonitrile;3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-benzenesulfonamide;9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9H-purine;9-(4-Fluoro-6-methoxy-pyridin-3-yl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9H-purine;6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9-(6-methoxy-2-methyl-pyridin-3-yl)-9H-purine;and2,5-Difluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundaccording to Formula (IV) (referred to herein as Group D5):4-[3-(4-Methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D6):3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;and2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundaccording to Formula (IV) (referred to herein as Group D7):4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D8):4-({Ethyl-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester; and4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundaccording to Formula (IV) (referred to herein as Group D9):4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-[1,7]naphthyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D10):4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Methylsulfanyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Isopropoxy-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Bromo-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Cyano-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-sulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Fluoro-6-methoxy-pyridin-3-yl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(6-Methoxy-2-methyl-pyridin-3-yl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-sulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-benzenesulfonamide;4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-quinoline;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinoline;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinoline;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-benzenesulfonamide;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-benzonitrile;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-N-propionyl-benzenesulfonamide;8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinoline;2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-benzenesulfonamide;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-quinoline;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinoline;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinoline;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-benzenesulfonamide;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-benzonitrile;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-N-propionyl-benzenesulfonamide;and8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinoline.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D11):4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Cyano-2-fluoro-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-sulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Fluoro-6-methoxy-pyridin-3-yl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-sulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzonitrile;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-y)-piperidin-4-yloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidine;2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzonitrile;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidine;and2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D12):3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidine;2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidine;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidine;and2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include include the followingcompounds according to Formula (IV) (referred to herein as Group D13):4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;and2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D14):4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;and2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide.

Examples of GPR119 agonists are described in U.S. Patent Application No.60/577,354, the disclosure of which is herein incorporated by referencein its entirety. Disclosed in U.S. Patent Application No. 60/577,354 asa GPR119 agonist is a compound of Formula (V):

or N-oxide thereof;

wherein:

-   -   A₁ and A₂ are independently C₁₋₃ alkylene optionally substituted        with one or more substituents selected independently from the        group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, and carboxy;    -   D is CR₁R₂ or NR₂, wherein R₁ is selected from the group        consisting of H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen and hydroxyl;    -   E is N, C or CR₃, wherein R₃ is H or C₁₋₆ alkyl;    -   is a single bond when E is N or CR₃, or a double bond when E is        C;    -   K is absent, C₃₋₆ cycloalkylene, or C₁₋₃ alkylene group        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ alkyl, C₁₋₆        alkoxy, carboxy, cyano, and halogen;    -   Q₁ is NR₄, O, S, S(O) or S(O)₂, wherein R₄ is H, C₁₋₆ acyl, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, or        C₃₋₇-cycloalkyl-C₁₋₃-alkylene, wherein said C₁₋₆ alkyl is        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,        hydroxylamino and nitro;    -   Q₂ is absent, NR₅, or O, wherein R₅ is H, C₁₋₆ acyl, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, or        C₃₋₇-cycloalkyl-C₁₋₃-alkylene, wherein said C₁₋₆ alkyl is        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,        hydroxylamino and nitro;    -   W is N or CH;    -   X is N or CR₆;    -   Y is N or CR₇;    -   Z is N or CR₈;    -   V is absent, C₁₋₃ heteroalkylene, or C₁₋₃ alkylene wherein each        are optionally substituted with one or more substituents        selected independently from the group consisting of C₁₋₃ alkyl,        C₁₋₆ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, and halogen;    -   R₆, R₇, and R₈ are each independently selected from the group        consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆        alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆        alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆        alkylthioureyl, C₁₋₆ alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆        alkoxycarbonyl, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆        haloalkylthio, hydroxyl, hydroxylamino and nitro, wherein said        C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl and C₃₋₆ cycloalkyl are        each optionally substituted with one or more substituents        independently selected from the group consisting of C₁₋₆ acyl,        C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆        alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆        alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆        alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl,        carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆        haloalkylthio, hydroxyl, hydroxylamino and nitro;    -   Ar is aryl or heteroaryl optionally substituted with R₉—R₁₃;    -   R₉ is selected from the group consisting of C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, aryl, arylcarbonyl, arylsulfonyl, di-C₁₋₆-alkylamino,        carbamimidoyl, C₁₋₆ alkoxycarbonyl, carboxamide, carboxy, cyano,        C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido,        guanidine, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆        haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio,        heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl,        hydroxylamino, nitro, C₃₋₆ oxo-cycloalkyl, phenoxy, sulfonamide,        sulfonic acid and thiol; and wherein each available R₉ is        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ acyl, C₁₋₆        acylsulfonamide, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆        alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl,        C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,        C₁₋₆ alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆ alkylthioureyl,        C₁₋₆ alkylureyl, amino, aryl, arylcarbonyl, arylsulfonyl,        di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide, carboxy,        cyano, C₃₋₆ cycloalkyl, di-C₁₋₆ alkylcarboxamide, di-C₁₋₆        alkylsulfonamide, di-C₁₋₆ alkylthiocarboxamido, C₁₋₆ haloalkoxy,        C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆-haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl,        heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl,        hydroxylamino, and nitro;    -   R₁₀—R₁₃ are independently selected from the group consisting of        C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,        C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆        alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆        alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl,        carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆        haloalkylthio, hydroxyl, hydroxylamino, nitro, and thiol; or two        adjacent groups together with the atoms to which they are bonded        form a 5, 6 or 7 member cycloalkyl, cycloalkenyl or heterocyclic        group wherein the 5, 6 or 7 member group is optionally        substituted with halogen or oxo; and    -   R₂ is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₄ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, aryl, arylcarbonyl, aryloxy, di-C₁₋₆-alkylamino,        carbamimidoyl, C₁₋₆ alkoxycarbonyl, C₃₋₇-cycloalkoxycarbonyl,        carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-        alkylthiocarboxamido, guanidine, C₁₋₆ haloalkoxy, C₁₋₆        haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆        haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl,        heteroaryl-C₁₋₃-alkylene, heteroarylcarbonyl, heteroaryloxy,        heterocycliccarboxamide, hydroxyl, hydroxylamino and nitro;        wherein each available R₂ is optionally substituted with one or        more substituents selected independently from the group        consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆        alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆        alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆        alkylthioureyl, C₁₋₆ alkylureyl, amino, aryl,        di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide, carboxy,        cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic,        heteroaryl, hydroxyl, hydroxylamino and nitro, and wherein C₁₋₆        alkyl is further optionally substituted with one or more        substituents selected independently from the group consisting of        C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide,        C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,        C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆        alkoxycarbonyl, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic,        hydroxyl, hydroxylamino and nitro.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in U.S. PatentApplication No. 60/577,354 include the following compounds according toFormula (V) (referred to herein as Group E1):4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine;{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-{[6-(2-Fluoro-4-methanesulfony-phenylamino)-pyrimidin-4-yl]-methyl-amino-piperidine-1-Carboxylic acid tert-butyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-benzylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-({Methyl-[6-(2-pyridin-4-yl-ethylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(2-pyridin-3-yl-ethylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[(2-Fluoro-4-methanesulfonyl-phenyl)-methyl-amino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[4-(2-Methanesulfonyl-ethyl)-phenylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethylsulfany-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Isopropylsulfanyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-methylsulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Dimethylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-methylsulfamoylmethyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-[1,2,4]triazol-1-ylmethyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(6-Methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-ylmethyl)-phenylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-pyrazol-1-yl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-Carboxylicacid tert-butyl ester;4-({[6-(2,2-Difluoro-benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[4-(morpholine-4-sulfonyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[2-(pyridine-2-carbonyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-5-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;N-Ethyl-3-fluoro-4-[6-(methyl-piperidin-4-ylmethyl-amino)-pyrimidin-4-ylamino]-benzenesulfonamide;3-Fluoro-N-isopropyl-4-[6-(methyl-piperidin-4-ylmethyl-amino)-pyrimidin-4[-ylamino]-benzenesulfonamide;4({[6-(3,4-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,6-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,3-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(2,3,5-trifluoro-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,4-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester; 4-[(Methyl-{6-[2-(1-oxy-pyridin-3-yl)-ethylamino]-pyrimidin4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[2-(1-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-[({6-[2-(2-Fluoro-phenoxy)-ethylamino]-pyrimidin4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[2-(2Chloro-phenoxy)-ethylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Chloro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[2-(4-Fluoro-phenoxy)-propylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethylsulfamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-isopropylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(5-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,6-Dimethoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;6-{6-[(1-tert-Butoxycarbonyl-piperidin-4-ylmethyl)-methyl-amino]-pyrimidin-4-ylamino}-nicotinicacid;4-({[6-(6-Acetylamino-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(5-Fluoro-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Cyano-2-ethyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Butyryl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(5-Bromo-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3-Bromo-5-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(5-trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Bromo-2-fluoro-phenylamino)-pyrimidin-4-y]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3-carboxy-4-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethoxycarbonyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid butyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid cyclopropylmethyl ester;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperazin-1-yl}-aceticacid ethyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-S-ylmethyl)-piperazin-1-yl]-pyrimidin-4-yl}-amine;4-({[6-(2,5-Difluoro-4-hydroxy-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Ethylcarbamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-[({6-[2-Fluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino-methyl)-piperidine-1-carboxylicacid 3-methyl-butyl ester;4-({[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;(5-Butyl-pyridin-2-yl)-[4-({[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidin-1-yl]-methanone;N-(2-Fluoro-4-methanesulfonyl-phenyl)-N′-(5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-N′-methyl-pyrimidine;-4,6-diamine;4-({[6-(4-Carbamimidoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid cyclobutyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;N-(2-Fluoro-4-methanesulfonyl-phenyl)-N′-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-4-ylmethyl]-N′-methyl-pyrimidine;-4,6-diamine;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid 1-ethyl-propyl ester;4-({Ethyl-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Amino-2,5-difluoro-phenoxy)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-4-methoxy-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-ethyl-amino)-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[6-(2,4,5-trifluoro-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-[(Ethyl-{6-[4-(N-ethylcarbamimidoyl)-2,5-difluoro-phenylamino]-pyrimidin-4-y-amino)-methyl]-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[5-(2-Amino-ethylamino)-4-Cyano-2-fluoro-phenylamino]-pyrimidin-4-yl}-ethyl-amino)-methyl]-piperidine-1-carboxylicacid isopropyl ester;{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-aceticacid methyl ester;3-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperazin-1-yl}-propionicacid ethyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isobutyl-phenyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isobutyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropoxy-phenyl)-piperazin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropoxy-phenyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(5-isopropoxy-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Dimethylaminomethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-(6-{4-[2-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-piperazin-1-yl}-pyrimidin-4-yl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(5-isopropoxy-pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;2,5-Difluoro-4-{6-[4-(4-isopropoxy-phenyl)-piperazin-1-yl]-pyrimidin-4-ylamino}-benzonitrile;4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester; and4-({[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester.

Specific examples of GPR119 agonists disclosed in U.S. PatentApplication No. 60/577,354 include the following compounds according toFormula (V) (referred to herein as Group E2):4-[6-(2-Fluoro-4-methanesulfony--phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(6-Chloro-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Bromo-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy-piperidin-1-yl}-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin--yl}-(6-methyl-pyridin-2-yl)-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-(6-fluoro-pyridin-2-yl)-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl-methanone;(5-Bromo-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;(5,6-Dichloro-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Hydroxy-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Cyano-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Chloro-4-Cyano-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Chloro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Fluoro-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-5-ethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Ethoxy-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Ethylsulfanyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Isopropylsulfanyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(5-Butyl-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[6-(5-Chloro-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Acetylamino-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(5-Fluoro-4-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methoxy-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Fluoro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Chloro-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(5-Fluoro-pyridin-2-ylamino)-pyrimidin-4-yloxyl-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Chloro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Methyl-pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-3-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Fluoro-4-hydroxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-isopropoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-[6-(5′-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;4-[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(Pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acidisopropyl ester;4-[6-(Pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acidisopropyl ester;4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Ethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Isopropylamino-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-6-propoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Iodo-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[Methyl-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;4-[6-(2-Phenyl-2H-pyrazol-3-ylamino)-pyrimidin4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-tert-Butyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-p-Tolyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methoxy-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Acetylamino-3-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Chloro-4-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-quinolin-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methylsulfanyl-benzothiazol-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Morpholin-4-yl-pyridin-3′-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Benzenesulfonyl-thiophen-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Piperidin-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methyl-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Cyano-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Methyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methoxy-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[Acetyl-(2-fluoro-4-methanesulfonyl-phenyl)-amino]-pyrimidin-4-yloxyl-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Carbamoyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(3,4-Difluoro-phenyl)-thiazol-2-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Oxazol-5-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Chloro-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[(5-Pyridin-2-yl-thiophen-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[5-(4-Chloro-phenyl)-2H-pyrazol-3′-ylamino]-pyrimidin4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(1-Oxo-indan-5-ylamino)-pyrimidin4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[5-(1-Methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-pyrimidin4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; 4-[6-(5-Bromo-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Ethynyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-5-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[5-(4-Methoxy-phenyl)-[1,3,4]thiadiazol-2-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3,5-Dimethyl-isoxazol-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-morpholin-4-y1-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Dimethylamino-ethoxy)-2,5-difluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,4-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[Acetyl-(4-methanesulfonyl-phenyl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(2,5-Difluoro-4-propoxy-phenyl)-{6-[1-(5-isopropyl-[1,2,4]oxadiazol-3′-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;4-{6-[2,5-Difluoro-4-(morpholin-4-ylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-methoxy-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2,5-Difluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Butylamino-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(3-methyl-butylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-2-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy-piperidine-1-carboxylic acid isopropyl ester;4-{6-[2-(2,5-Difluoro-phenoxy)-ethylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-fluoro-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[4-(2-Fluoro-4-methanesulfony1-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[4-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2004/050046 (published as WO 2005/061489), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/GB2004/050046 as a GPR119 agonist is acompound of Formula (VI):R¹-A-V—B—R²   (VI)

wherein:

-   -   V is a 5-membered heteroaryl ring containing up to four        heteroatoms selected from O, N and S, optionally substituted by        C₁₋₆ alkyl;    -   A is —CH═CH— or (CH₂)_(n);        -   B is —CH═CH— or (CH₂)_(n), where one of the CH₂ groups may            be replaced by O, NR⁵, S(O)_(m), C(O) or C(O)NR¹²;    -   n is independently 0, 1, 2 or 3;    -   m is independently 0, 1 or 2;    -   R¹ is 3- or 4-pyridyl, 4- or 5-pyrimidinyl or 2-pyrazinyl, any        of which may be optionally substituted by one or more        substituents selected from halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, aryl, OR⁶, CN, NO₂,        S(O)_(m)R⁶, CON(R⁶)₂, N(R⁶)₂, NR¹⁰COR⁶, NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, a        4- to 7-membered heterocyclyl group or a 5- or 6-membered        heteroaryl group;    -   R² is 4- to 7-membered cycloalkyl substituted by R³, C(O)OR³,        C(O)R³ or S(O)₂R³, or 4- to 7-membered heterocyclyl, containing        one or two nitrogen atoms which is unsubstituted or substituted        by C(O)OR⁴, C(O)R³, S(O)₂R³, C(O)NHR⁴, P(O)(OR¹¹)₂ or a 5- or        6-membered nitrogen containing heteroaryl group;    -   R³ is C₃8 alkyl, C₃-8 alkenyl or C₃-8 alkynyl, any of which may        be optionally substituted with up to 5 fluoro or chloro atoms,        and may contain a CH₂ group that may be replaced by O, or C₃₋₇        cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkylC₃₋₇        cycloalkyl, C₁₋₄ alkylaryl, C₁₋₄ alkylheterocyclyl or C₁₋₄        alkylheteroaryl, any of which may be optionally substituted with        one or more substituents selected from halo, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, OR⁶, CN, CO₂C₁₋₆ alkyl, N(R⁶)₂ and NO₂;    -   R⁴ is C₂₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, any of which may        be optionally substituted with up to 5 fluoro or chloro atoms,        and may contain a CH₂ group that may be replaced by O, or C₃₋₇        cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkylC₃₋₇        cycloalkyl, C₁₋₄ alkylaryl, C₁₋₄ alkylheterocyclyl or C₁₋₄        alkylheteroaryl, any of which may be substituted with one or        more substituents selected from halo, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, OR⁶, CN, CO₂C₁₋₆ alkyl, N(R⁶)₂ and NO₂;    -   R⁵ is hydrogen, C(O)R⁷, S(O)₂R⁸, C₃₋₇ cycloalkyl or C₁₋₄ alkyl        optionally substituted by OR⁶, C₃₋₇ cycloalkyl, aryl,        heterocyclyl or heteroaryl, wherein the cyclic groups may be        substituted with one or more substituents selected from halo,        C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, OR⁶, CN, N(R⁶)₂ and NO₂;    -   R⁶ are independently hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl,        aryl, heterocyclyl or heteroaryl, wherein the cyclic groups may        be substituted with one or more substituents selected from halo,        C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, OR⁹, CN, SO₂CH₃, N(R¹⁰)2 and NO₂;        or a group (N(R¹⁰)₂ may form a 4- to 7-membered heterocyclic        ring optionally containing a further heteroatom selected from O        and NR¹⁰;    -   R⁷ is hydrogen, C₁₋₄ alkyl, OR⁶, N(R⁶)₂, aryl or heteroaryl;    -   R⁸is C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, aryl or heteroaryl;    -   R⁹ is hydrogen, C₁₋₂ alkyl or C₁₋₂ fluoroalkyl;    -   R¹⁰ is hydrogen or C₁₋₄ alkyl;    -   R¹¹ is phenyl; and    -   R¹² is hydrogen, C₁₋₄ alkyl or C₃₋₇ cycloalkyl.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/GB2004/050046 include the following compoundsaccording to Formula (VI) (referred to herein as Group F1):4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidtert-butyl ester;3-(3-Pyridin4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Pentylcyclohexylmethyl)-[1,2,4]oxadiazol-3-yl]pyridine;trans-2-Chloro4-[5-(4-pentylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[5-(4-Pentylcyclohexane)-[1,2,4]oxadiazol-3-ylmethyl]pyridine;4-(3-Pyridin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylicacid tert-butyl ester;trans-3-[5-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-3-ylmethyl]pyridine;4-[5-(4-Butylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;4-[5-(4-n-Propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[5-(4-Pentylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;4-[2-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)-ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;3-[5-(4-Propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;3-[5-(4-Butylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine-2-carboxylicacid methylamide;trans-4-[5-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine-2-carboxylicacid amide;trans-4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-3-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Methyl-3-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-6-methyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine-2-carbonitrile;trans-2-Chloro-3-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-6-methyl-3-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Methyl-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-3-Methyl-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2,6-Dichloro-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-6-methoxy-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-5-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]-2-[1,2,4]triazol-1-ylpyridine;2-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyrazine;4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyrimidine;trans-5-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine-2-carbonitrile;trans-5-Chloro-2-methylsulfanyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyrimidine;trans-2-Fluoro-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Fluoro4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Imidazol-1-yl-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Methyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-3-Methyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-4-{2-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]vinyl}pyridine;4-(5-Pyridin-4-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-3-yl-vinyl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-3-yl-vinyl)-[1,2,4]oxadiazol-3-yl]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-3-yl-vinyl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-4-yl-vinyl)-[1,2,4]oxadiazol-3-yl]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Pyridin-4-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester;4-{5-[2-(2-Cyanopyridin-4-yl)ethyl]-[1,2,4]oxadiazol-3-yl}piperidine-1-carboxylicacid tert-butyl ester;4-{5-[2-(2-Cyanopyridin-4-yl)ethyl]-[1,2,4]oxadiazol-3-ylmethoxy}piperidine-1-carboxylicacid tert-butyl ester;4-{5-[2-(2-Cyanopyridin4-yl)ethyl]-[1,2,4]oxadiazol-3-ylmethyl}piperidine-1-carboxylicacid tert-butyl ester;4-(5-Piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidisobutyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid2-methoxyethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidethyl ester;3,3-Dimethyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]butan-1-one;2-Cyclopentyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]ethanone;4-{5-[1-(Butane-1-sulfonyl)piperidin-4-yl]-[1,2,4]oxadiazol-3-yl}pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidpropylamide;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidtert-butylamide;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid cyclopentyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid benzyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid isobutyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid ethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid cycloheptyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid methyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-methoxy-ethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid isopropyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-methoxy-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2,2,2-trichloroethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-Chloro-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-ethyl-hexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid propyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid hexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2,2-dimethylpropyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid naphthalen-1-yl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-methoxy-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 3-trifluoromethylphenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid prop-2-ynyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid but-2-ynyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid pentyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid p-tolyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-Chloro-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid naphthalen-2-yl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-methoxycarbonyl-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-fluoro-phenyl ester;3-Methyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]-butan-1-one;Phenyl-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]methanone;1-[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]butan-1-one;2,2-Dimethyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]propan-1-one;Cyclopentyl-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]methanone;[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]-p-tolylmethanone;3,3-Dimethyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]butan-1-one;4-{5-[1-(Butane-1-sulfonyl)piperidin-4-yloxymethyl]-[1,2,4]oxadiazol-3-yl}pyridine;4-{5-[1-(Propane-1-sulfonyl)piperidin-4-yloxymethyl]-[1,2,4]oxadiazol-3-yl}pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butylamide;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid o-tolylamide;trans-4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acidpropyl ester;trans-4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acidbutyl ester;trans-4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acidisobutyl ester;trans-4-[5-(4-Propoxymethylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[5-(4-Butoxymethylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;cis-4-[5-(3-Butoxymethylcyclopentyl)-[1,2,4]oxadiazol-3-yl]pyridine;cis-4-[5-(3-Propoxymethylcyclopentyl)-[1,2,4]oxadiazol-3-yl]pyridine;cis-4-[5-(3-Butoxymethylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl;2-[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]pyrazine;2-[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]pyrimidine;(4-Pentylcyclohexyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;(4-Pentylcyclohexyl-methyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;4-[(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-{[3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]amino}-piperidine-1-carboxylicacid tert-butyl ester;Methyl-(4-pentylcyclohexyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;Methyl-(4-pentylcyclohexylmethyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;4-[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Ethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Propyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Cyclopropylmethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Butyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-{[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[Ethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]ethylamino}-piperidine-1-carboxylicacid tert-butyl ester;4-[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid cyclopentyl ester;4-{[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid 2,2,2-trichloroethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxymethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)piperazine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethanesulfonyl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Pyridin-4-yl-[1,3,4]oxadiazol-2-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester; 3-Pyridin-4-yl-[1,2,4]oxadiazole-5-Carboxylicacid (4-pentylcyclohexyl)amide;[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]phosphonicacid diphenyl ester;4-(4-Pyridin-4-yl-thiazol-2-ylmethoxy)piperidine-1-carboxylic acidtert-butyl ester;4-(2-Pyridin-4-yl-thiazol-4-ylmethyl)piperidine-1-carboxylic acidtert-butyl ester;trans-4-[5-(4-Pentyl-cyclohexyl)-[1,3,4]thiadiazol-2-yl]pyridine;4-(5-Pyridin-4-yl-[1,3,4]thiadiazol-2-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Pyridin-4-yl-4H-[1,2,4]triazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[2-(5-Pyridin-4-yl-isoxazol-3-yl)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-(5-Pyridin-4-yl-isoxazol-3-ylmethoxy)piperidine-1-carboxylic acidtert-butyl ester;4-(5-Pyridin-4-yl-isoxazol-3-ylmethyl)piperidine-1-carboxylic acidtert-butyl ester;4-[2-(1-Methyl-5-pyridin-4-yl-1H-pyrazol-3-yl)ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[2-(2-Methyl-5-pyridin-4-yl-2H-pyrazol-3-yl)ethyl]-piperidine-1-carboxylicacid tert-butyl ester;(E)-4-{5-[2-(2-Cyanopyridin-4-yl)vinyl]-[1,2,4]oxadiazol-3-yl}piperidine-1-carboxylicacid tert-butyl ester;4-{5-[2-(2H-Tetrazol-5-yl)pyridine-4-yl]-[1,2,4]oxadiazol-3-ylmethoxy}-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid isopropyl ester; and4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid phenyl ester.

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (I).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (II).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (III).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (IV).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (V).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (VI).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (VI), provided that the compound is not4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine,4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidbutyl ester, 4-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine,3-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine, or3-[5-(4-propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine.

In one aspect of the present invention, the GPR119 agonist is selectedfrom Group A1, Group B1, Group B2, Group B3, Group B4, Group B5, GroupC1, Group C2, Group C3, Group C4, Group C5, Group C6, Group C7, GroupC8, Group C9, Group C10, Group D1, Group D2, Group D3, Group D4, GroupD5, Group D6, Group D7, Group D8, Group D9, Group D10, Group D11, GroupD12, Group D13, Group D14, Group E1, Group E2 or Group F1.

In one aspect, the GPR119 agonist is selected from the left column ofTable B.

Specific examples of GPR119 agonists include 2-(pyridine-4-yl)ethylthiobenzoate and L-α-lysophosphatidylcholine oleoyl, as disclosed in EP1338651, the disclosure of which is herein incorporated by reference inits entirety.

Examples of GPR119 agonists may be found in International Application WO03/026661, the disclosure of which is herein incorporated by referencein its entirety. GPR119 agonists disclosed in WO 03/026661 include butare not limited to the compounds in Table C. TABLE C Cmpd No. ChemicalStructure Chemical Name 1C

[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-meth- yl-amine 2C

[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-p-tolyl-amine 3C

[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-(4-meth-oxy-phenyl)-amine 4C

[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-phe- nyl-amine 5C

[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-cyclo- hexyl-amine 6C

5-[2-(4-Bromo-phenyl)-6-eth- yl-pyrimidin-4-ylamino]-pen- tan-1-ol 7C

3-[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-ylamino]-pro- pionitrile 8C

[2-(4-Bromo-phenyl)-6-ethyl-py- rimidin-4-yl]-(4-fluoro- benzyl)-amine9C

[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-yl]-[2-(4-chloro-phenyl)-ethyl]-amine 10C

[2-(4-Bromo-phenyl)-6-ethyl-py- rimidin-4-yl]-pyridin-2-yl- methyl-amine11C

[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-py-ridin-3-ylmethyl-amine 12C

3-{[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-ylamino]-meth-yl}-1H-pyridin-2-one 13C

4-{[2-(4-Bromo-phenyl)-6-eth- yl-pyrimidin-4-ylamino]-meth-yl}-1H-pyridin-2-one 14C

4-{2-[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-ylamino]-eth-yl}-1H-pyridin-2-one 15C

[2-(3-Chloro-4-fluoro-phenyl)-6-eth- yl-pyrimidin-4-yl]-(1,1-di-oxo-hexahydro-116-thio- pyran-4-yl)-amine 16C

[6-Methyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine 17C

[6-Ethyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine 18C

[6-Methyl-2-(2,4,5-trifluoro- phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine 19C

4-{4-Methyl-6-[2-(1-oxy- pyridin-3-yl)-ethylamino]-py-rimidin-2-yl}-benzonitrile 20C

2-[4-(6-Methyl-2-phenyl- pyrimidin-4-ylamino)-phenyl]-eth- anol 21C

[2-(3-Chloro-phenyl)-6-meth- yl-pyrimidin-4-yl]-meth- yl-amine 22C

2-{[2-(4-Bromo-phenyl)-6-meth- yl-pyrimidin-4-yl]-meth-yl-amino}-ethanol; compound with methane

Examples of GPR119 agonists may be found in International Application JP2004269468, the disclosure of which is herein incorporated by referencein its entirety. GPR119 agonists disclosed in JP 2004269468 include butare not limited to the compounds in Table D. TABLE D Cmpd No. ChemicalStructure Chemical Name 1D

3-[6-Ethyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-pro-pane-1,2-diol 2D

(S)-3-[6-Methyl-2-(2,3,5-tri- fluoro-phenyl)-pyrimidin-4-yl-amino]-propane-1,2-diol 3D

(S)-3-[2-(4-Bromo-3-fluoro- phenyl)-6-methyl-pyrimidin-4-yl-amino]-propane-1,2-diol 4D

(R)-3-[6-Ethyl-2-(3,4,5-tri- fluoro-phenyl)-pyrimidin-4-yl-amino]-propane-1,2-diol 5D

(R)-3-[2-(3-Chloro-4-fluoro- phenyl)-6-ethyl-pyrimidin-4-yl-amino]-propane-1,2-diol 6D

(R)-3-[2-(4-Bromo-2,5-di- fluoro-phenyl)-5-fluoro-6-meth-yl-pyrimidin-4-ylamino]-pro- pane-1,2-diol 7D

(R)-3-[2-(4-Chloro-2,5-di- fluoro-phenyl)-6-di-fluoromethyl-pyrimidin-4-yl- amino]-propane-1,2-diol

Examples of GPR119 agonists may be found in International Application JP2004269469, the disclosure of which is herein incorporated by referencein its entirety. GPR119 agonists disclosed in JP 2004269469 include butare not limited to the compounds in Table E. TABLE E Cmpd No. ChemicalStructure Chemical Name 1D

5-{2-[2-(4-Bromo-phenyl)-6-eth- yl-pyrimidin-4-ylamino]-eth-yl}-1H-pyridin-2-one 2E

5-{2-[6-Methyl-2-(2,4,5-tri- fluoro-phenyl)-pyrimidin-4-yl-amino]-ethyl}-1H-pyridin-2-one 3E

4-{2-[2-(4-Chloro-2,5-di- fluoro-phenyl)-6-ethyl-pyrimidin-4-ylamino]-ethyl}-1H-py- ridin-2-one 4E

6-Chloro-4-{2-[6-methyl-2-(2,4,5-tri- fluoro-phenyl)-py-rimidin-4-ylamino]-ethyl}-1H-py- ridin-2-one 5E

4-{1-Hydroxy-2-[6-methyl-2-(2,4,5-tri- fluoro-phenyl)-py-rimidin-4-ylamino]-ethyl}-1H-py- ridin-2-one 6E

4-{1-Methyl-2-[6-methyl-2-(2,4,5-tri- fluoro-phenyl)-py-rimidin-4-ylamino]-ethyl}-1H-py- ridin-2-one

In one aspect of the present invention, the GPR119 agonist is a compoundwhich comprises Group A1, Group B1, Group B2, Group B3, Group B4, GroupB5, Group C1, Group C2, Group C3, Group C4, Group C5, Group C6, GroupC7, Group C8, Group C9, Group C10, Group D1, Group D2, Group D3, GroupD4, Group D5, Group D6, Group D7, Group D8, Group D9, Group D10, GroupD11, Group D12, Group D13, Group D14, Group E1, Group E2 or Group F1.

In one aspect, the GPR119 agonist is not identical to a compoundincluded in the left column of Table B.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in International Application No. PCT/US2004/001267.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in International Application No. PCT/GB2004/050046.

In one aspect, the GPR119 agonist is not identical to a compound ofFormula (I).

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group A1.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in International Application No. PCT/US2004/005555.

In one aspect, the GPR119 agonist is not identical to a compound ofFormula (II).

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group B1, Group B2, Group B3, Group B4 or Group B5.

In one aspect, the GPR119 agonist is not identical to a compound, takenindividually, which comprises any one of Group B1, Group B2, Group B3,Group B4 or Group B5 taken individually.

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group B1. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group B2. In one aspect, the GPR119agonist is not identical to a compound which comprises Group B3. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group B4. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group B5.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in International Application No. PCT/US04/022327.

In one aspect, the GPR119 agonist is not identical to a compound ofFormula (III).

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group C1, Group C2, Group C3, Group C4, Group C5, Group C6,Group C7, Group C8, Group C9 or Group C10.

In one aspect, the GPR119 agonist is not identical to a compound, takenindividually, which comprises any one of Group C1, Group C2, Group C3,Group C4, Group C5, Group C6, Group C7, Group C8, Group C9 or Group C10taken individually.

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group C1. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group C2. In one aspect, the GPR119agonist is not identical to a compound which comprises Group C3. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group C4. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group C5. In one aspect, the GPR119agonist is not identical to a compound which comprises Group C6. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group C7. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group C8. In one aspect, the GPR119agonist is not identical to a compound which comprises Group C9. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group C10

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in International Application No. PCT/US04/022417.

In one aspect, the GPR119 agonist is not identical to a compound ofFormula (IV).

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group D1, Group D2, Group D3, Group D4, Group D5, Group D6,Group D7, Group D8, Group D9, Group D10, Group D11, Group D12, Group D13or Group D14.

In one aspect, the GPR119 agonist is not identical to a compound, takenindividually, which comprises any one of Group D1, Group D2, Group D3,Group D4, Group D5, Group D6, Group D7, Group D8, Group D9, Group D10,Group D11, Group D12, Group D13 or Group D14 taken individually.

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group D1. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group D2. In one aspect, the GPR119agonist is not identical to a compound which comprises Group D3. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group D4. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group D5. In one aspect, the GPR119agonist is not identical to a compound which comprises Group D6. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group D7. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group D8. In one aspect, the GPR119agonist is not identical to a compound which comprises Group D9. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group D10. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group D11. In one aspect, the GPR119agonist is not identical to a compound which comprises Group D12. In oneaspect, the GPR119 agonist is not identical to a compound whichcomprises Group D13. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group D14.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in U.S. Patent Application No. 60/577,354.

In one aspect, the GPR119 agonist is not identical to a compound ofFormula (V).

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group E1 or Group E2.

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group E1. In one aspect, the GPR119 agonist is not identicalto a compound which comprises Group E2.

In one aspect, the GPR119 agonist is not identical to a compound ofFormula (VI).

In one aspect, the GPR119 agonist is not identical to a compound whichcomprises Group F1.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in EP 1338651.

In one aspect, the GPR119 agonist is not identical to2-(pyridine-4-yl)ethyl thiobenzoate.

In one aspect, the GPR119 agonist is not identical toL-α-lysophosphatidylcholine oleoyl.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in WO 03/026661.

In one aspect, the GPR119 agonist is not identical to a compound inTable C.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in JP 2004269468.

In one aspect, the GPR119 agonist is not identical to a compound inTable D.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in JP 2004269469.

In one aspect, the GPR119 agonist is not identical to a compound inTable E.

In one aspect, the GPR119 agonist is not identical to a compounddisclosed in WO 2005/061489.

In one aspect, the GPR119 agonist is not identical to4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine. In one aspect, theGPR119 agonist is not identical to4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidbutyl ester. In one aspect, the GPR119 agonist is not identical to4-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine. In one aspect,the GPR119 agonist is not identical to3-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine. In one aspect,the GPR119 agonist is not identical to3-[5-(4-propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine.

In one aspect of the present invention, any one or more GPR119 agonistcan be excluded from any embodiment of the present invention.

In one aspect of the present invention, any one or more GPR119 agonistwhich comprises Group A1, Group B1, Group B2, Group B3, Group B4, GroupB5, Group C1, Group C2, Group C3, Group C4, Group C5, Group C6, GroupC7, Group C8, Group C9, Group C10, Group D1, Group D2, Group D3, GroupD4, Group D5, Group D6, Group D7, Group D8, Group D9, Group D10, GroupD11, Group D12, Group D13, Group D14, Group E1, Group E2 or Group F1 canbe excluded from any embodiment of the present invention.

In one aspect of the present invention, the GPR119 agonist has an EC50of less than about 10 FM, less than about 1 μM, less than about 100 nM,less than about 75 nM, less than about 50 nM, less than about 25 nM,less than about 20 nM, less than about 15 nM, less than about 10 nM,less than about 5 nM, less than about 4 nM, less than about 3 nM, lessthan about 2 nM, or less than about 1 nM. Preferably the GPR119 agonisthas an EC50 of less than about 50 nM, less than about 25 nM, less thanabout 20 nM, less than about 15 nM, less than about 10 nM, less thanabout 5 nM, less than about 4 nM, less than about 3 nM, less than about2 nM, or less than about 1 nM.

In one aspect of the present invention, the GPR119 agonist is aselective GPR119 agonist, wherein the selective GPR119 agonist has aselectivity for GPR119 over corticotrophin-releasing factor-1 (CRF-1)receptor of at least about 100-fold.

In one aspect of the present invention, the GPR119 agonist is orallyactive.

In one aspect of the present invention, the GPR119 agonist is an agonistof human GPR119.

DPP-IV Inhibitors

The class of DPP-IV inhibitors useful in the novel therapeuticcombinations of the present invention include compounds which exhibit anacceptably high affinity for DPP-IV. The DPP-IV inhibitor orpharmaceutically acceptable salt may be any DPP-IV inhibitor, morepreferably a selective dipeptidyl peptidase inhibitor, and mostpreferably a selective DPP-IV inhibitor.

Examples of DPP-IV inhibitors are described in Villhauer et al., J MedChem (2003) 46:2774-2789, for LAF237; Ahren et al, J Clin EndocrinolMetab (2004) 89:2078-2084; Villhauer et al., J Med Chem (2002)45:2362-2365 for NVP-DPP728; Ahren et al, Diabetes Care (2002)25:869-875 for NVP-DPP728; Peters et al., Bioorg Med Chem Lett (2004)14:1491-1493; Caldwell et al., Bioorg Med Chem Lett (2004) 14:1265-1268;Edmondson et al., Bioorg Med Chem Lett (2004) 14:5151-5155; and Abe etal., J Nat Prod (2004) 67:999-1004; the disclosure of each of which isherein incorporated by reference in its entirety.

Specific examples of DPP-IV inhibitors include, but are not limited to,dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide,isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl,O-benzoyl hydroxylamine, as described e.g. in U.S. Pat. No. 6,303,661,the disclosure of which is herein incorporated by reference in itsentirety.

Examples of DPP-IV inhibitors may be found in U.S. Pat. Nos. 6,869,947,6,867,205, 6,861,440, 6,849,622, 6,812,350, 6,803,357, 6,800,650,6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995, 6,617,340,6,699,871, 6,573,287, 6,432,969, 6,395,767, 6,380,398, 6,303,661,6,242,422, 6,166,063, 6,100,234, 6,040,145, the disclosure of each ofwhich is herein incorporated by reference in its entirety. Examples ofDPP-IV inhibitors may be found in U.S. Pat. Appl. Nos. 2005059724,2005059716, 2005043292, 2005038020, 2005032804, 2005004205, 2004259903,2004259902, 2004259883, 2004254226, 2004242898, 2004229926, 2004180925,2004176406, 2004138214, 2004116328, 2004110817, 2004106656, 2004097510,2004087587, 2004082570, 2004077645, 2004072892, 2004063935, 2004034014,2003232788, 2003225102, 2003216450, 2003216382, 2003199528, 2003195188,2003162820, 2003149071, 2003134802, 2003130281, 2003130199, 2003125304,2003119750, 2003119738, 2003105077, 2003100563, 2003087950, 2003078247,2002198205, 2002183367, 2002103384, 2002049164, 2002006899, thedisclosure of each of which is herein incorporated by reference in itsentirety.

Examples of DPP-IV inhibitors may be found in International ApplicationsWO 2005/087235, WO 2005/082348, WO 2005/082849, WO 2005/079795, WO2005/075426, WO 2005/072530, WO 2005/063750, WO 2005/058849, WO2005/049022, WO 2005/047297, WO 2005/044195, WO 2005/042488, WO2005/040095, WO 2005/037828, WO 2005/037779, WO 2005/034940, WO2005/033099, WO 2005/032590, WO 2005/030751, WO 2005/030127, WO2005/026148, WO 2005/025554, WO 2005/023762, WO 2005/020920, WO05/19168, WO 05/12312, WO 05/12308, WO 05/12249, WO 05/11581, WO05/09956, WO 05/03135, WO 05/00848, WO 05/00846, WO 04/112701, WO04/111051, WO 04/111041, WO 04/110436, WO 04/110375, WO 04/108730, WO04/104216, WO 04/104215, WO 04/103993, WO 04/103276, WO 04/99134, WO04/96806, WO 04/92128, WO 04/87650, WO 04/87053, WO 04/85661, WO04/85378, WO 04/76434, WO 04/76433, WO 04/71454, WO 04/69162, WO04/67509, WO 04/64778, WO 04/58266, WO 04/52362, WO 04/52850, WO04/50022, WO 04/50658, WO 04/48379, WO 04/46106, WO 04/43940, WO04/41820, WO 04/41795, WO 04/37169, WO 04/37181, WO 04/33455, WO04/32836, WO 04/20407, WO 04/18469, WO 04/18468, WO 04/18467, WO04/14860, WO 04/09544, WO 04/07468, WO 04/07446, WO 04/04661, WO04/00327, WO 03/106456, WO 03/104229, WO 03/101958, WO 03/101448, WO03/99279, WO 03/95425, WO 03/84940, WO 03/82817, WO 03/80633, WO03/74500, WO 03/72556, WO 03/72528, WO 03/68757, WO 03/68748, WO03/57666, WO 03/57144, WO 03/55881, WO 03/45228, WO 03/40174, WO03/38123, WO 03/37327, WO 03/35067, WO 03/35057, WO 03/24965, WO03/24942, WO 03/22871, WO 03/15775, WO 03/04498, WO 03/04496, WO03/02530, WO 03/02596, WO 03/02595, WO 03/02593, WO 03/02553, WO03/02531, WO 03/00181, WO 03/00180, WO 03/00250, WO 02/83109, WO02/83128, WO 02/76450, WO 02/68420, WO 02/62764, WO 02/55088, WO02/51836, WO 02/38541, WO 02/34900, WO 02/30891, WO 02/30890, WO02/14271, WO 02/02560, WO 01/97808, WO 01/96295, WO 01/81337, WO01/81304, WO 01/68603, WO 01/55105, WO 01/52825, WO 01/34594, WO00/71135, WO 00/69868, WO 00/56297, WO 00/56296, WO 00/34241, WO00/23421, WO 00/10549, WO 99/67278, WO 99/62914, WO 99/61431, WO99/56753, WO 99/25719, WO 99/16864, WO 98/50066, WO 98/50046, WO98/19998, WO 98/18763, WO 97/40832, WO 95/29691, WO 95/15309, WO93/10127, WO 93/08259, WO 91/16339, EP 1517907, EP 1513808, EP 1492777,EP 1490335, EP 1489088, EP 1480961, EP 1476435, EP 1476429, EP 1469873,EP 1465891, EP 1463727, EP 1461337, EP 1450794, EP 1446116, EP 1442049,EP 1441719, EP 1426366, EP 1412357, EP1406873, EP 1406872, EP 1406622,EP 1404675, EP 1399420, EP 1399471, EP 1399470, EP 1399469, EP 1399433,EP 1399154, EP 1385508, EP 1377288, EP 1355886, EP 1354882, EP 1338592,EP 1333025, EP 1304327, EP 1301187, EP 1296974, EP 1280797, EP 1282600,EP 1261586, EP 1258476, EP 1254113, EP 1248604, EP 1245568, EP 1215207,EP 1228061, EP 1137635, EP 1123272, EP 1104293, EP 1082314, EP 1050540,EP 1043328, EP 0995440, EP 0980249, EP 0975359, EP 0731789, EP 0641347,EP 0610317, EP 0528858, CA 2466870, CA 2433090, CA 2339537, CA 2289125,CA 2289124, CA 2123128, DD 296075, DE 19834591, DE 19828113, DE19823831, DE 19616486, DE 10333935, DE 10327439, DE 10256264, DE10251927, DE 10238477, DE 10238470, DE 10238243, DE 10143840, FR2824825, FR 2822826, JP2005507261, JP 2005505531, JP 2005502624, JP2005500321, JP 2005500308, JP2005023038, JP 2004536115, JP 2004535445,JP 2004535433, JP 2004534836, JP 2004534815, JP 2004532220, JP2004530729, JP 2004525929, JP 2004525179, JP 2004522786, JP 2004521149,JP 2004503531, JP 2004315496, JP 2004244412, JP 2004043429, JP2004035574, JP 2004026820, JP 2004026678, JP 2004002368, JP 2004002367,JP 2003535898, JP 2003535034, JP 2003531204, JP 2003531191, JP2003531118, JP 2003524591, JP 2003520849, JP 2003327532, JP 2003300977,JP 2003238566, JP 2002531547, JP 2002527504, JP 2002517401, JP2002516318, JP 2002363157, JP 2002356472, JP 2002356471, JP 2002265439,JP 2001510442, JP 2000511559, JP 2000327689, JP 2000191616, JP1998182613, JP 1998081666, JP 1997509921, JP 1995501078, JP 1993508624,the disclosure of each of which is herein incorporated by reference inits entirety.

In one aspect of the present invention, the DPP-IV inhibitor isvaline-pyrrolidide [Deacon et al, Diabetes (1998) 47:764769; thedisclosure of which is herein incorporated by reference in itsentirety].

In one aspect of the present invention, the DPP-IV inhibitor is3-(L-Isoleucyl)thiazolidine (isoleucine-thiazolidide).Isoleucine-thiazolidide may be found in JP 2001510442, WO 97/40832, U.S.Pat. No. 6,303,661, and DE 19616486, the disclosure of each of which isherein incorporated by reference in its entirety.Isoleucine-thiazolidide is described as an orally active and selectiveDPP-IV inhibitor [Pederson et al, Diabetes (1998) 47:1253-1258; thedisclosure of which is herein incorporated by reference in itsentirety].

In one aspect of the present invention, the DPP-IV inhibitor is1-[2-[5-Cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine(NVP-DPP728). NVP-DPP728 may be found in WO 98/19998 and JP 2000511559,the disclosure of each of which is herein incorporated by reference inits entirety. NVP-DPP728 is described as an orally active and selectiveDPP-IV inhibitor [Villhauer et al, J Med Chem (2002) 45:2362-2365].

In one aspect of the present invention, the DPP-IV inhibitor is3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one(MK-0431). MK-0431 may be found in EP 1412357, WO 03/04498, U.S. Pat.No. 6,699,871, and US 2003100563, the disclosure of each of which isherein incorporated by reference in its entirety. MK-0431 is describedas an orally active and selective DPP-IV inhibitor [Weber et al,Diabetes (2004) 53(Suppl.2):A 151, 633-P (Abstract), the disclosure ofwhich is herein incorporated by reference in its entirety].

In one aspect of the present invention, the DPP-IV inhibitor is(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine(LAF237). LAF237 may be found in U.S. Pat. No. 6,166,063, WO 00/34241,EP 1137635, and JP 2002531547, the disclosure of each of which is hereinincorporated by reference in its entirety. LAF237 is described as anorally active and selective DPP-IV inhibitor [Villhauer et al, J MedChem (2003) 46:2774-2789].

In one aspect of the present invention, the DPP-IV inhibitor is(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(BMS-477118).

In one aspect of the present invention, the DPP-IV inhibitor is[1-[2(S)-Amino-3-methylbutyryl]pyrrolidin-2(R)-yl]boronic acid (PT-100).

In one aspect of the present invention, the DPP-IV inhibitor isGSK-823093.

In one aspect of the present invention, the DPP-IV inhibitor isPSN-9301.

In one aspect ot the present invention, the DPP-IV inhibitor is T-6666.

In one aspect of the present invention, the DPP-IV inhibitor is SYR-322.

In one aspect of the present invention, the DPP-IV inhibitor is SYR-619.

In one aspect of the present invention, the DPP-IV inhibitor isCR-14023.

In one aspect of the present invention, the DPP-IV inhibitor isCR-14025.

In one aspect of the present invention, the DPP-IV inhibitor isCR-14240.

In one aspect of the present invention, the DPP-IV inhibitor isCR-13651.

In one aspect of the present invention, the DPP-IV inhibitor isNNC-72-2138.

In one aspect of the present invention, the DPP-IV inhibitor is NN-7201.

In one aspect of the present invention, the DPP-IV inhibitor isPHX-1149.

In one aspect of the present invention, the DPP-IV inhibitor isPHX-1004.

In one aspect of the present invention, the DPP-IV inhibitor isSNT-189379.

In one aspect of the present invention, the DPP-IV inhibitor isGRC-8087.

In one aspect of the present invention, the DPP-IV inhibitor is PT-630.

In one aspect of the present invention, the DPP-IV inhibitor is SK-0403.

In one aspect of the present invention, the DPP-IV inhibitor isGSK-825964.

In one aspect of the present invention, the DPP-IV inhibitor is TS-021.

In one aspect of the present invention, the DPP-IV inhibitor isGRC-8200.

In one aspect of the present invention, the DPP-IV inhibitor isGRC-8116.

In one aspect of the present invention, the DPP-IV inhibitor isFE107542.

In one aspect of the present invention, the DPP-IV inhibitor is selectedfrom the right column of Table B.

In one aspect of the present invention, the DPP-IV inhibitor is not adipeptide derivative.

In one aspect of the present invention, the DPP-IV inhibitor is not adipeptide mimetic.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to valine-pyrrolidide.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to alanine-pyrrolidide.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to 3-(L-Isoleucyl)thiazolidine (isoleucine-thiazolidide).

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to N-valyl propyl, O-benzoyl hydroxylamine.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine(NVP-DPP728).

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one(MK-043 1).

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine(LAF237).

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(BMS-477118).

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to [1-[2(S)-Amino-3-methylbutyryl]pyrrolidin-2(R)-yl]boronicacid (PT-100).

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to GSK-823093.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to PSN-9301.

In one aspect ot the present invention, the DPP-IV inhibitor is notidentical to T-6666.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to SYR-322.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to SYR-619.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to CR-14023.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to CR-14025.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to CR-14240.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to CR-13651.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to NNC-72-2138.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to NN-7201.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to PHX-1 149.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to PHX-1004.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to SNT-189379.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to GRC-8087.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to PT-630.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to SK-0403.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to GSK-825964.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to TS-021.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to GRC-8200.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to GRC-8116.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to FE107542.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to a compound included in the right column of Table B.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to a compound disclosed in a U.S. patent having a U.S. Pat.No. selected from the group consisting of U.S. Pat. Nos. 6,869,947,6,867,205, 6,861,440, 6,849,622, 6,812,350, 6,803,357, 6,800,650,6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995, 6,617,340,6,699,871, 6,573,287, 6,432,969, 6,395,767, 6,380,398, 6,303,661,6,242,422, 6,166,063, 6,100,234, and 6,040,145.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to a compound disclosed in a U.S. patent application having aU.S. Pat. Appln. No. selected from the group consisting of 2005059724,2005059716, 2005043292, 2005038020, 2005032804, 2005004205, 2004259903,2004259902, 2004259883, 2004254226, 2004242898, 2004229926, 2004180925,2004176406, 2004138214, 2004116328, 2004110817, 2004106656, 2004097510,2004087587, 2004082570, 2004077645, 2004072892, 2004063935, 2004034014,2003232788, 2003225102, 2003216450, 2003216382, 2003199528, 2003195188,2003162820, 2003149071, 2003134802, 2003130281, 2003130199, 2003125304,2003119750, 2003119738, 2003105077, 2003100563, 2003087950, 2003078247,2002198205, 2002183367, 2002103384, 2002049164, and 2002006899.

In one aspect of the present invention, the DPP-IV inhibitor is notidentical to a compound disclosed in an International Applicationselected from the group consisting of WO 2005/087235, WO 2005/082348, WO2005/082849, WO 2005/079795, WO 2005/075426, WO 2005/072530, WO2005/063750, WO 2005/058849, WO 2005/049022, WO 2005/047297, WO2005/044195, WO 2005/042488, WO 2005/040095, WO 2005/037828, WO2005/037779, WO 2005/034940, WO 2005/033099, WO 2005/032590, WO2005/030751, WO 2005/030127, WO 2005/026148, WO 2005/025554, WO2005/023762, WO 2005/020920, WO 05/19168, WO 05/12312, WO 05/12308, WO05/12249, WO 05/11581, WO 05/09956, WO 05/03135, WO 05/00848, WO05/00846, WO 04/112701, WO 04/111051, WO 04/111041, WO 04/110436, WO04/110375, WO 04/108730, WO 04/104216, WO 04/104215, WO 04/103993, WO04/103276, WO 04/99134, WO 04/96806, WO 04/92128, WO 04/87650, WO04/87053, WO 04/85661, WO 04/85378, WO 04/76434, WO 04/76433, WO04/71454, WO 04/69162, WO 04/67509, WO 04/64778, WO 04/58266, WO04/52362, WO 04/52850, WO 04/50022, WO 04/50658, WO 04/48379, WO04/46106, WO 04/43940, WO 04/41820, WO 04/41795, WO 04/37169, WO04/37181, WO 04/33455, WO 04/32836, WO 04/20407, WO 04/18469, WO04/18468, WO 04/18467, WO 04/14860, WO 04/09544, WO 04/07468, WO04/07446, WO 04/04661, WO 04/00327, WO 03/106456, WO 03/104229, WO03/101958, WO 03/101448, WO 03/99279, WO 03/95425, WO 03/84940, WO03/82817, WO 03/80633, WO 03/74500, WO 03/72556, WO 03/72528, WO03/68757, WO 03/68748, WO 03/57666, WO 03/57144, WO 03/55881, WO03/45228, WO 03/40174, WO 03/38123, WO 03/37327, WO 03/35067, WO03/35057, WO 03/24965, WO 03/24942, WO 03/22871, WO 03/15775, WO03/04498, WO 03/04496, WO 03/02530, WO 03/02596, WO 03/02595, WO03/02593, WO 03/02553, WO 03/02531, WO 03/00181, WO 03/00180, WO03/00250, WO 02/83109, WO 02/83128, WO 02/76450, WO 02/68420, WO02/62764, WO 02/55088, WO 02/51836, WO 02/38541, WO 02/34900, WO02/30891, WO 02/30890, WO 02/14271, WO 02/02560, WO 01/97808, WO01/96295, WO 01/81337, WO 01/81304, WO 01/68603, WO 01/55105, WO01/52825, WO 01/34594, WO 00/71135, WO 00/69868, WO 00/56297, WO00/56296, WO 00/34241, WO 00/23421, WO 00/10549, WO 99/67278, WO99/62914, WO 99/61431, WO 99/56753, WO 99/25719, WO 99/16864, WO98/50066, WO 98/50046, WO 98/19998, WO 98/18763, WO 97/40832, WO95/29691, WO 95/15309, WO 93/10127, WO 93/08259, WO 91/16339, EP1517907, EP 1513808, EP 1492777, EP 1490335, EP 1489088, EP 1480961, EP1476435, EP 1476429, EP 1469873, EP 1465891, EP 1463727, EP 1461337, EP1450794, EP 1446116, EP 1442049, EP 1441719, EP 1426366, EP 1412357,EP1406873, EP 1406872, EP 1406622, EP 1404675, EP 1399420, EP 1399471,EP 1399470, EP 1399469, EP 1399433, EP 1399154, EP 1385508, EP 1377288,EP 1355886, EP 1354882, EP 1338592, EP 1333025, EP 1304327, EP 1301187,EP 1296974, EP 1280797, EP 1282600, EP 1261586, EP 1258476, EP 1254113,EP 1248604, EP 1245568, EP 1215207, EP 1228061, EP 1137635, EP 1123272,EP 1104293, EP 1082314, EP 1050540, EP 1043328, EP 0995440, EP 0980249,EP 0975359, EP 0731789, EP 0641347, EP 0610317, EP 0528858, CA 2466870,CA 2433090, CA 2339537, CA 2289125, CA 2289124, CA 2123128, DD 296075,DE 19834591, DE 19828113, DE 19823831, DE 19616486, DE 10333935, DE10327439, DE 10256264, DE 10251927, DE 10238477, DE 10238470, DE10238243, DE 10143840, FR 2824825, FR 2822826, JP2005507261, JP2005505531, JP 2005502624, JP 2005500321, JP 2005500308, JP2005023038,JP 2004536115, JP 2004535445, JP 2004535433, JP 2004534836, JP2004534815, JP 2004532220, JP 2004530729, JP 2004525929, JP 2004525179,JP 2004522786, JP 2004521149, JP 2004503531, JP 2004315496, JP2004244412, JP 2004043429, JP 2004035574, JP 2004026820, JP 2004026678,JP 2004002368, JP 2004002367, JP 2003535898, JP 2003535034, JP2003531204, JP 2003531191, JP 2003531118, JP 2003524591, JP 2003520849,JP 2003327532, JP 2003300977, JP 2003238566, JP 2002531547, JP2002527504, JP 2002517401, JP 2002516318, JP 2002363157, JP 2002356472,JP 2002356471, JP 2002265439, JP 2001510442, JP 2000511559, JP2000327689, JP 2000191616, JP 1998182613, JP 1998081666, JP 1997509921,JP 1995501078, and JP 1993508624.

In one aspect of the present invention, any one or more DPP-IV inhibitorcan be excluded from any embodiment of the present invention.

In one aspect of the present invention, the DPP-IV inhibitor has an IC50of less than about 10 μM, less than about 1 μM, less than about 100 nM,less than about 75 nM, less than about 50 nM, less than about 25 nM,less than about 20 nM, less than about 15 nM, less than about 10 nM,less than about 5 nM, less than about 4 nM, less than about 3 nM, lessthan about 2 nM, or less than about I nM. Preferably the DPP-IVinhibitor has an IC50 of less than about 50 nM, less than about 25 nM,less than about 20 nM, less than about 15 nM, less than about 10 nM,less than about 5 nM, less than about 4 nM, less than about 3 nM, lessthan about 2 nM, or less than about 1 nM.

In one aspect of the present invention, the DPP-IV inhibitor a selectiveDPP-IV inhibitor, wherein the selective DPP-IV inhibitor has aselectivity for human plasma DPP-IV over one or more of PPCE, DPP-II,DPP-8 and DPP-9 of at least about 10-fold, more preferably of at leastabout 100-fold, and most preferably of at least about 1000-fold.

In one aspect of the present invention, the DPP-IV inhibitor is orallyactive. In one aspect of the present invention, the DPP-IV inhibitor isan inhibitor of human DPP-IV.

Combination of GPR1I9 Agonist and DPP-IV Inhibitor

By way of illustration and not limitation, an exemplary combination ofGPR119 agonist and DPP-IV inhibitor in accordance with the presentinvention is provided by selecting a GPR119 agonist from the left columnof Table B and a DPP-IV inhibitor from the right column of Table B. Itis expressly contemplated that each individual combination of GPR119agonist and DPP-IV inhibitor provided by selecting a GPR119 agonist fromthe left column of Table B and a DPP-IV inhibitor from the right columnof Table B is a separate embodiment within the scope of the presentinvention. TABLE B GPR119 Agonist DPP-IV Inhibitor[6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro- valine-pyrrolididepyrimidin-4-yl]-(4-methanesulfonyl-phenyl)- amine{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-3-(L-Isoleucyl)thiazolidine pyrimidin-4-yl]-piperazin-1-yl}-acetic acidethyl (isoleucine-thiazolidide) ester(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3- 1-[2-[5-cyanopyridin-2-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-yl)amino]ethylamino]acetyl-2-cyano-(S)- 5-nitro-pyrimidin-4-yl}-aminepyrrolidine (NVP-DPP728) 6′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4- carboxylic acid ethylester (2,4,5-trifluorophenyl)butan-1-one (MK-0431)1-[4-(4-Acetyl-3′-nitro-3,4,5,6-tetrahydro-2H-(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-ethanone cyano-(S)-pyrrolidine(LAF237) 6′-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-3′-(1S,3S,5S)-2-[2(S)-Amino-2-(3-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-hydroxyadamantan-1-yl)acetyl]-2- carboxylic acid ethyl esterazabicyclo[3.1.0]hexane-3-carbonitrile (BMS-477118)1-[5-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-[1-[2(S)-Amino-3-methylbutyryl]pyrrolidin-2(R)- piperidine-4-carboxylicacid ethyl ester yl]boronic acid (PT-100)1-{5-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-2- GSK-823093nitro-phenyl}-piperidine-4-carboxylic acid ethyl ester1-[5-(2-Amino-4-ethanesulfonyl-phenoxy)-2- PSN-9301nitro-phenyl]-piperidine-4-carboxylic acid ethyl ester5-Bromo-1-[4-nitro-3-(4-propyl-piperidin-1-yl)- T-6666phenyl]-1H-pyridin-2-one 6′-Benzenesulfonylamino-3′-nitro-3,4,5,6-SYR-322 tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester6′-(Benzenesulfonyl-methyl-amino)-3′-nitro- SYR-6193,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4- carboxylic acid ethyl ester6′-(Benzenesulfonyl-butyl-amino)-3′-nitro- CR-140233,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4- carboxylic acid ethyl ester1-[5-(4-Benzoyl-phenylamino)-2-nitro-phenyl]- CR-14025piperidine-4-carboxylic acid ethyl ester{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)- CR-14240phenylamino]-phenyl}-phenyl-methanone3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro- CR-13651pyrimidin-4-yloxymethyl]-pyrrolidine-1- carboxylic acid tert-butyl ester4-[5-Cyano-6-(6-methylsulfanyl-pyridin-3- NNC-72-2138ylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid tert-butylester 4-[5-Cyano-6-(6-methanesulfonyl-pyridin-3- NN-7201ylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid tert-butylester 4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro- PHX-1149pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester(4-Methanesulfonyl-phenyl)-[5-nitro-6- PHX-1004(piperidin-4-yloxy)-pyrimidin-4-yl]-amine1-{4-[6-(4-Methanesulfonyl-phenylamino)-5- SNT-189379nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3- dimethyl-butan-1-one4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro- GRC-8087pyrimidin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl esterN-(4-Methanesulfonyl-phenyl)-5-nitro-N′- PT-630piperidin-4-yl-pyrimidine-4,6-diamine1-{4-[6-(4-Methanesulfonyl-phenylamino)-5- SK-0403nitro-pyrimidin-4-ylamino]-piperidin-1-yl}- ethanone4-[6-(4-Cyano-2-fluoro-phenylamino)-5-ethynyl- GSK-825964pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-8-(3-Aminopiperidin-1-yl)-N2,7-dibenzyl-1-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- methylguaninetrifluoroacetate carboxylic acid isopropyl ester4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-N-[2-[2-[8-(3-Aminopiperidin-1-yl)-7-(2-5-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamino}-butynyl)-3-methylxanthin-1- 3-fluoro-benzonitrileyl]acetyl]phenyl]formamide 4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-8-[3(R)-Aminopiperidin-1-yl]-7-(2-butynyl)-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-methyl-1-(quinazolin-2-ylmethyl)xanthine carboxylic acid isobutyl ester1-[4-(1-Benzyl-azetidin-3-yloxy)-6-(6-8-(3-Aminopiperidin-1-yl)-1-(benzo[c]-1,8-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-naphthyridin-6-ylmethyl)-7-(2-butynyl)-3- 5-yl]-ethanone methylxanthine4-[5-Cyano-6-(6-propylamino-pyridin-3-2-[8-[3(R)-Aminopiperidin-1-yl]-7-(2-butynyl)-ylamino)-pyrimidin-4-yloxy]-piperidine-1-3-methylxanthin-1-yl]-N-(2-pyridyl)acetamide carboxylic acid isopropylester 4-({[6-(2-Fluoro-4-methanesulfonyl-2-(3-Aminopiperidin-1-yl)-3-(2-butynyl)-5-phenylamino)-5-methyl-pyrimidin-4-yl]-(quinoxalin-6-ylmethyl)-4,5-dihydro-3H-isopropyl-amino}-methyl)-piperidine-1- imidazo[4,5-d]pyridazin-4-onecarboxylic acid tert-butyl ester4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(1S,3S,5S)-2-[2(S)-Amino-4,4-(3-methoxy-propyl)-piperidin-4-yloxy]-5-methyl-dimethylpentanoyl]-2-azabicyclo[3.1.0]hexane- pyrimidine3(S)-carbonitrile trifluoroacetate1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-N1-(1-Cyanoethyl)-N1,3-dimethyl-L-valinamide5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3- methoxy-propan-2-ol4-{6-[2-Fluoro-4-(5-isopropoxymethyl-(1S,3S,5S)-2-[2(S)-Amino-2-[1-(3,3-[1,2,4]oxadiazol-3-yl)-phenoxy]-5-methyl-dimethylbutyryl)piperidin-4-yl]acetyl]-2-pyrimidin-4-yloxy}-piperidine-1-carboxylic acidazabicyclo[3.1.0]hexane-3-carbonitrile isopropyl ester4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-5-2-[7-(2-Butynyl)-1-(2-phenylethyl)-8-(1-methyl-pyrimidin-4-yloxy]-piperidine-1- piperazinyl)xanthin-3-yl]-N-(2-carboxylic acid isopropyl ester propynyl)acetamide hydrochloride{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-2-[7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(1-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(2-piperazinyl)-6,7-dihydro-1H-purin-2-yloxy]-N-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-methanone methylbenzamidetrifluoroacetate (6-Amino-pyridin-3-yl)-{4-[6-(2-fluoro-4-2-[3-(2-Butynyl)-4-oxo-2-(1-piperazinyl)-4,5-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-dihydro-3H-imidazo[4,5-d]pyridazin-5- 4-yloxy]-piperidin-1-yl}-methanoneylmethyl]benzonitrile trifluoroacetate4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-N-[1(S)-[2(S)-Cyanopyrrolidin-1-ylcarbonyl]-4-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-(pyrazin-2-ylcarboxamido)butyl]carbamic acid 1-methyl)-piperidine-1-carboxylic acid tert-butyl acetoxyethyl ester ester4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-2(S),4-Diamino-1-(4-thiomorpholinyl)butan-1-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}- onemethyl)-piperidine-1-carboxylic acid isopropyl ester4-({[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-1-[Perhydroindol-2(S)-ylcarbonyl]azetidine-2(S)-methyl-pyrimidin-4-yl]-isopropyl-amino}- carbonitrilemethyl)-piperidine-1-carboxylic acid isopropyl ester4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-1-(2-Benzothiazolyl)-1-[1-[(2S,3aS,7aS)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1-perhydroindol-2-ylcarbonyl]pyrrolidin-2(S)- carboxylic acid isopropylester yl]methanone hydrochloride 4-[1-(4-Methanesulfonyl-phenyl)-1H-1-[2(S)-Amino-2-cyclohexylacetyl]-4-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-methylazetidine-2-carbonitrile hydrochloride carboxylic acid tert-butylester 4-[1-(4-Methanesulfonyl-phenyl)-3-methyl-1H-6-[2-[2-[5(S)-Cyano-4,5-dihydro-1H-pyrazol-1-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-yl]-2-oxoethylamino]ethylamino]pyridine-3- carboxylic acid tert-butylester carbonitrile 4-[1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-6-[2-[2-[2(S)-Cyano-4(S)-fluoropyrrolidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-2-oxoethylamino]-2-methylpropylamino]-N,N- piperidine-1-carboxylic acidtert-butyl ester dimethylpyridine-3-sulfonamide4-({[1-(2,5-Difluoro-phenyl)-1H-pyrazolo[3,4-trans-N-[4-[1(S)-Amino-2-[3(S)-fluoropyrrolidin-d]pyrimidin-4-yl]-methyl-amino}-methyl)-1-yl]-2-oxoethyl]cyclohexyl]-2,4- piperidine-1-carboxylic acidtert-butyl ester difluorobenzenesulfonamide2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-2(S)-Amino-1-(1-pyrrolidinyl)-2-[4-(thiazol-2-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-ylamino)cyclohexyl]ethanone trifluoroacetate1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-N-[(1R,3R)-3-[1(S)-Amino-2-oxo-2-(1-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-pyrrolidinyl)ethyl]cyclopentyl]-4- 1-yl}-1-(3-fluoro-phenyl)-ethanone(methylsulfonyl)benzenesulfonamide4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-3(R)-Amino-1-(6-benzyl-3-methyl-5,6,7,8-6-yloxy]-piperidine-1-carboxylic acid isobutyltetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3,4- esterdifluorophenyl)butan-1-one {4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-trans-N-[4-[1(S)-Amino-2-oxo-2-(1-purin-6-yloxy]-piperidin-1-yl}-pyridin-3-yl-pyrrolidinyl)ethyl]cyclohexyl]-2,4- methanone difluorobenzenesulfonamide4-[9-(4-Methanesulfonyl-phenyl)-9H-purin-6-3(R)-Amino-4-(2,5-difluorophenyl)-1-[4- yloxy]-piperidine-1-carboxylicacid tert-butyl hydroxy-2-(trifluoromethyl)-5,6,7,8- estertetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1- one4-[9-(2-Fluoro-4-propionylsulfamoyl-phenyl)-N-[(1R,3R)-3-[1(S)-Amino-2-oxo-2-(1-9H-purin-6-yloxy]-piperidine-1-carboxylic acidpyrrolidinyl)ethyl]cyclopentyl]-2- isopropyl ester(methylsulfonamido)ethanesulfonamide4-[9-(4-Cyano-2-fluoro-phenyl)-9H-purin-6-2-[4-[3(R)-Amino-4-(2-fluorophenyl)butyryl]-yloxy]-piperidine-1-carboxylic acid isopropyl3(R)-benzylpiperazin-1-yl]-N-[3- ester(methylsulfonamido)phenyl]acetamide4-[9-(2-Fluoro-4-sulfamoyl-phenyl)-9H-purin-6-3(R)-Amino-1-(3-thiazolidinyl)-4-(2,4,5- yloxy]-piperidine-1-carboxylicacid isopropyl trifluorophenyl)butan-1-one ester4-[3-(4-Methanesulfonyl-phenyl)-3H-4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]- 3(R)-methyl-1,4-diazepan-2-onepiperidine-1-carboxylic acid tert-butyl ester3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-3(S)-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-dimethyl-4-oxo-2(S)-[4-([1,2,4]triazolo[1,5-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidinea]pyridin-6-yl)phenyl]butyramide3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-3(R)-Amino-1-[2-(trifluoromethyl)-5,6,7,8-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-7-yl]-4-d]pyrimidin-3-yl}-N-propionyl- (2,4,5-trifluorophenyl)butanonehydrochloride benzenesulfonamide3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-2(S)-Amino-3(S)-(4-fluorophenyl)-1-(3-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5- thiazolidinyl)butan-1-oned]pyrimidin-3-yl}-benzonitrile4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-7-[3(R)-Amino-4-(2,5-difluorophenyl)butyryl]-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2- acid tert-butyl estercarboxylic acid ethyl ester 4-({Ethyl-[3-(4-methanesulfonyl-phenyl)-3(R)-Amino-1-(8-chloro-1,2,3,4-isoxazolo[4,5-d]pyrimidin-7-yl]-amino}-methyl)-tetrahydropyrazino[1,2-a]benzimidazol-2-yl)-4- piperidine-1-carboxylicacid tert-butyl ester (2,5-difluorophenyl)butan-1-one trifluoroacetate4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-3(R)-Amino-4-(2,5-difluorophenyl)-1-[2-(4-d]pyrimidin-7-ylsulfanyl]-piperidine-1-fluorophenyl)-4,5,6,7-tetrahydrothiazolo[4,5- carboxylic acid tert-butylester c]pyridin-5-yl]butan-1-one4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-2-[4-[2-[3(R)-Amino-4-(2-fluorophenyl)butyryl]-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic1,2,3,4-tetrahydroisoquinolin-3- acid isopropyl esterylcarboxamidomethyl]phenyl]acetic acid4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-3(S)-Amino-2-oxopiperidin-1-ylphosphonic[1,7]naphthyridin-4-yloxy]-piperidine-1- diamide hydrochloridecarboxylic acid isopropyl ester4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-2-[2-(5-Nitropyridin-2-ylamino)ethylamino]-1-quinolin-4-yloxy]-piperidine-1-carboxylic acid (1-pyrrolidinyl)ethanonedihydrochloride isopropyl ester4-[8-(4-Methylsulfanyl-phenyl)-quinolin-4-2-[8-(3-Aminopiperidin-1-yl)-1,3- yloxy]-piperidine-1-carboxylic acidisopropyl dimethylxanthin-7-ylmethyl]benzonitrile ester hemisuccinate4-[8-(4-Methanesulfonyl-phenyl)-quinolin-4-2(S)-Amino-2-cyclohexyl-1-(3,3,4,4- yloxy]-piperidine-1-carboxylic acidisopropyl tetrafluoropyrrolidin-1-yl)ethanone hydrochloride ester4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-2(S)-Amino-2-cyclohexyl-1-(3-fluoropyrrolidin-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1- 1-yl)ethanone carboxylicacid isopropyl ester 4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-Amino-1-cyclopentyl-3-methylpentan-1-onepyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1- hydrochloride carboxylicacid isopropyl ester 4-[8-(4-Cyano-2-fluoro-phenyl)-pyrido[3,4-4-Amino-5-oxo-5-(1-pyrrolidinyl)pentanamided]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3- 1-[2-[1,1-Dimethyl-2-(6-phenylpyridin-2-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-ylamino)ethylamino]acetyl]pyrrolidine-2(S)- pyrazolo[1,5-a]pyrimidinecarbonitrile hydrochloride 3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol- (7R*,8S*,13bS*)-7-Butyl-11,12-dimethoxy-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-,3,4,4a,6,7,8,9,9a,13b-decahydro-1H-pyrido[1,2-3-yl}-N-propionyl-benzenesulfonamide f]phenanthridin-8-amine3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-(Aminomethyl)-6-(2,4-dichlorophenyl)-2-(3,5-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-dimethoxyphenyl)pyrimidin-4-amine 13-yl}-benzonitrile4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-1-3-(Aminomethyl)-4-(2,4-dichlorophenyl)-7,8-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-dimethoxy-5H-indeno[1,2-b]pyridin-2-amine piperidine-1-carboxylic acidisopropyl ester 4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1-5-(Aminomethyl)-6-(2,4-dichlorophenyl)-N2-(2-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-methoxyethyl)-N2-methylpyrimidine-2,4-diamine piperidine-1-carboxylicacid isopropyl ester 4-[3-(4-Cyano-2-fluoro-phenyl)-1-methyl-1H-4,4-Difluoro-1-[2-[exo-8-(2-pyrimidinyl)-8-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1- azabicyclo[3.2.1]oct-3-carboxylic acid isopropyl esterylamino]acetyl]pyrrolidine-2(S)-carbonitrile4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-exo-3-[2-[8-(2-Pyrimidinyl)-8-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]- azabicyclo[3.2.1]oct-3-piperidine-1-carboxylic acid isopropyl esterylamino]acetyl]thiazolidine-4(R)-carbonitrile4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-1-[2-[3-(2,3-Dihydro-1H-isoindol-2-yl)-1,1-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-dimethyl-3-oxopropylamino]acetyl]pyrrolidine- piperidine-1-carboxylicacid isopropyl ester 2(S)-carbonitrile4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-2H-8-(3-Aminoperhydroazepin-1-yl)-3-methyl-7-(2-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-methylbenzyl)-2,3,6,7-tetrahydro-1H-purine-2,6- carboxylic acidisopropyl ester dione 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-8-[3(R)-Aminopiperidin-1-yl]-7-(5-fluoro-2-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-methylbenzyl)-1,3-dimethylxanthine pyrimidine{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-2-[2-(3-Aminopiperidin-1-yl)-6,7-dimethoxy-4-piperidin-1-yl]-pyrimidin-4-yl}-(4- oxo-3,4-dihydroquinazolin-3-methanesulfonyl-phenyl)-amine ylmethyl]benzonitrile4-{[6-(2-Fluoro-4-methanesulfonyl-1-[2(S)-Amino-3,3-dimethylbutyryl]-4(S)-phenylamino)-pyrimidin-4-yl]-methyl-amino}-fluoropyrrolidine-2(S)-carbonitrile hydrochloridepiperidine-1-carboxylic acid tert-butyl ester4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-2-[3-(Aminomethyl)-4-butoxy-2-(2,2-pyrimidin-4-yloxy]-piperidine-1-carboxylic aciddimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6- tert-butyl esteryloxy]acetamide hydrochloride(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-3-(3-Chloroimidazo[1,2-a]pyridin-2-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-ylmethylsulfonyl)-N,N-dimethyl-1H-1,2,4- 4-yloxy]-pyrimidin-4-yl}-amine;4-[6-(2-Fluoro- triazole-1-carboxamide4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester(6-Chloro-pyridin-2-yl)-{4-[6-(2-fluoro-4-6-Chloro-2-isobutyl-4-phenylquinolin-3-methanesulfonyl-phenylamino)-pyrimidin-4- ylmethylamineyloxy]-piperidin-1-yl}-methanone[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-yl]-trans-1-[2-[4-(1,3-Dioxo-2,3-dihydro-1H- methyl-amine isoindol-2-yl)cyclohexylamino]acetyl]pyrrolidine-2(S)- carbonitrile hydrochloride[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-yl]-trans-4-[2-[4(R)-Cyanothiazolidin-3-yl]-2- p-tolyl-amineoxoethylamino]-N,N- dimethylcyclohexanecarboxamide hydrochloride[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-yl]-N-(5-Chloropyridin-2-yl)-2-[4-[1-[2-(4- (4-methoxy-phenyl)-aminecyanothiazolidin-3-yl)-2- oxoethyl]hydrazino]piperidin-1-yl]acetamidetris(trifluoroacetate) [2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-yl]-6-[2-[2-[2(S)-Cyanoazetidin-1-yl]-2- phenyl-amineoxoethylamino]ethylamino]pyridine-3- carbonitrile dihydrochloride[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-yl]-4(S)-Fluoro-1-[2-[1-(2-hydroxyacetyl)-4- cyclohexyl-aminemethylpiperidin-4-ylamino]acetyl]pyrrolidine- 2(S)-carbonitrile fumarate5-[2-(4-Bromo-phenyl)-6-ethyl-pyrimidin-4- TS-021 ylamino]-pentan-1-ol3-[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4- GRC-8200ylamino]-propionitrile [2-(4-Bromo-phenyl)-6-ethyl-pyrimidin-4-yl]-(4-GRC-8116 fluoro-benzyl)-amine[2-(4-Bromo-phenyl)-6-ethyl-pyrimidin-4-yl]-[2- FE107542(4-chloro-phenyl)-ethyl]-amine[2-(4-Bromo-phenyl)-6-ethyl-pyrimidin-4-yl]- pyridin-2-ylmethyl-amine[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-yl]- pyridin-3-ylmethyl-amine3-{[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-ylamino]-methyl}-1H-pyridin-2-one4-{[2-(4-Bromo-phenyl)-6-ethyl-pyrimidin-4-ylamino]-methyl}-1H-pyridin-2-one4-{2-[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one[2-(3-Chloro-4-fluoro-phenyl)-6-ethyl-pyrimidin-4-yl]-(1,1-dioxo-hexahydro-116-thiopyran-4-yl)- amine[6-Methyl-2-(3,4,5-trifluoro-phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine[6-Ethyl-2-(3,4,5-trifluoro-phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine[6-Methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine4-{4-Methyl-6-[2-(1-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-2-yl}-benzonitrile2-[4-(6-Methyl-2-phenyl-pyrimidin-4-ylamino)- phenyl]-ethanol[2-(3-Chloro-phenyl)-6-methyl-pyrimidin-4-yl]- methyl-amine2-{[2-(4-Bromo-phenyl)-6-methyl-pyrimidin-4- yl]-methyl-amino}-ethanol;compound with methane 3-[6-Ethyl-2-(3,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol (S)-3-[6-Methyl-2-(2,3,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol(S)-3-[2-(4-Bromo-3-fluoro-phenyl)-6-methyl-pyrimidin-4-ylamino]-propane-1,2-diol(R)-3-[6-Ethyl-2-(3,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol(R)-3-[2-(3-Chloro-4-fluoro-phenyl)-6-ethyl-pyrimidin-4-ylamino]-propane-1,2-diol(R)-3-[2-(4-Bromo-2,5-difluoro-phenyl)-5-fluoro-6-methyl-pyrimidin-4-ylamino]-propane-1,2-diol(R)-3-[2-(4-Chloro-2,5-difluoro-phenyl)-6-difluoromethyl-pyrimidin-4-ylamino]-propane- 1,2-diol5-{2-[2-(4-Bromo-phenyl)-6-ethyl-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one5-{2-[6-Methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one4-{2-[2-(4-Chloro-2,5-difluoro-phenyl)-6-ethyl-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one6-Chloro-4-{2-[6-methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H- pyridin-2-one4-{1-Hydroxy-2-[6-methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H- pyridin-2-one4-{1-Methyl-2-[6-methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H- pyridin-2-one4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5- ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester 4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5- ylmethoxy)piperidine-1-carboxylicacid cyclopentyl ester 4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylic acid 2,2,2- trichloroethyl ester4-[Ethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylic acid tert-butyl ester4-[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylic acid cyclopentyl ester4-{[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}piperidine-1-carboxylic acid 2,2,2-trichloroethylester

Additionally, compounds of the invention, including those illustrated inTABLE B, encompass all pharmaceutically acceptable salts, solvates, andhydrates thereof. See, e.g., Berge et al (1977), Journal ofPharmaceutical Sciences 66:1-19; and Polymorphism in PharmaceuticalSolids (1999) Brittain, ed., Marcel Dekker, Inc.; the disclosure of eachof which is herein incorporated by reference in its entirety.

As relates to the combination therapy described above, the compoundsaccording to the invention can be administered in any suitable way.Suitable routes of administration include oral, nasal, rectal,transmucosal, transdermal, or intestinal administration, parenteraldelivery, including intramuscular, subcutaneous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intravenous, intraperitoneal, intranasal, intrapulmonary (inhaled) orintraocular injections using methods known in the art. Other suitableroutes of administration are aerosol and depot formulation. Sustainedrelease formulations, particularly depot, of the invented medicamentsare expressly contemplated. In certain preferred embodiments, thecompounds according to the present invention are administered orally.The compounds according to the present invention can be made up in solidor liquid form, such as tablets, capsules, powders, syrups, elixirs andthe like, aerosols, sterile solutions, suspensions or emulsions, and thelike. In certain embodiments, one or both of the GPR119 agonist and theDPP-IV inhibitor are administered orally.

Formulations for oral administration may be in the form of aqueoussolutions and suspensions, in addition to solid tablet and capsuleformulations. The aqueous solutions and suspensions may be prepared fromsterile powders or granules. The compounds may be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious buffers. Other adjuvants are well and widely known in the art.

It will be appreciated that the GPR119 agonist and the DPP-IV inhibitormay be present as a combined preparation for simultaneous, separate orsequential use for the treatment or prevention of diabetes or acondition related thereto. Such combined preprations may be, forexample, in the form of a twin pack.

It will therefore be further appreciated that the invention contemplatesa product comprising or consisting essentially of a GPR119 agonist and aDPP-IV inhibitor as a combined preparation for simultaneous, separate orsequential use in the prevention or treatment of diabetes or a conditionrelated thereto.

A combination of the present invention comprising or consistingessentially of a GPR119 agonist and a DPP-IV inhibitor can be preparedby mixing the GPR119 agonist and the DPP-IV inhibitor either alltogether or independently with a pharmaceutically acceptable carrier,excipient, binder, dilutent, etc. as described herein, and administeringthe mixture or mixtures either orally or non-orally as a pharmaceuticalcomposition(s).

It will therefore be further appreciated that the GPR119 agonist and theDPP-IV inhibitor or pharmaceutical composition can be administered inseparate dosage forms or in a single dosage form.

It is further appreciated that when the GPR119 agonist and the DPP-IVinhibitor are in separate dosage forms, GPR119 agonist and DPP-IVinhibitor can be administered by different routes.

Pharmaceutical compositions of the GPR119 agonist and DPP-IV inhibitor,either individually or in combination, may be prepared by methods wellknown in the art, e.g., by means of conventional mixing, dissolving,granulation, dragee-making, levigating, emulsifying, encapsulating,entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Suitablepharmaceutically acceptable carriers are available to those in the art[see, e.g., Remington: The Science and Practice of Pharmacy, (Gennaro etal., eds.), 20^(th) Edition, 2000, Lippincott Williams & Wilkins; andHandbook of Pharmaceutical Excipients (Rowe et al., eds), 4^(th)Edition, 2003, Pharmaceutical Press; the disclosure of each of which isherein incorporated by reference in its entirety]. Proper formulation isdependent upon the route of administration chosen. The term “carrier”material or “excipient” material herein means any substance, not itselfa therapeutic agent, used as a carrier and/or dilutent and/or adjuvant,or vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral admininstration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improved appearance of the composition.Acceptable excipients include stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate,pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches,gelatin, cellulosic materials, such as cellulose esters of alkanoicacids and cellulose alkyl esters, low melting wax cocoa butter orpowder, polymers, such as polyvinyl-pyrrolidone, polyvinyl alcohol, andpolytheylene glycols, and other pharmaceutically acceptable materials.The components of the pharmaceutical composition can be encapsulated ortableted for convenient administration.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When the GPR119 agonist and the DPP-IV inhibitor are in separate dosageforms, it is understood that a pharmaceutically acceptable carrier usedfor the GPR119 agonist formulation need not be identical to apharmaceutically acceptable carrier used for the DPP-IV inhibitorformulation.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum Arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as welll as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid polyethyleneglycols, cremophor, capmul, medium or long chain mon-, di- ortriglycerides. Stabilizers may be added in these formulations, also.

Additionally, the GPR119 agonist and DPP-IV inhibitor may be deliveredusing a sustained-release system. Various sustained-release materialshave been established and are well known to those skilled in the art.Sustained-release tablets or capsules are particularly preferred. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate may be employed. The dosage form may also be coated by thetechniques described in the U.S. Pat. Nos. 4,256,108, 4,166,452, and4,265,874 to form osmotic therapeutic tablets for controlled release.

It is expressly contemplated that a combination therapy of the presentinvention may be administered or provided alone or in combination withone or more other pharmaceutically or physiologically acceptablecompound. In one aspect of the present invention, the otherpharmaceutically or physiologically acceptable compound is not a GPR119agonist and is not a DPP-IV inhibitor. In one aspect of the presentinvention, the other pharmaceutically or physiologically acceptablecompound is a pharmaceutical agent selected from the group consisting ofsulfonylurea (e.g., glibenclamide, glipizide, gliclazide, glimepiride),meglitinide (e.g., repaglinide, nateglinide), biguanide (e.g.,metformin), alpha-glucosidase inhibitor (e.g., acarbose, epalrestat,miglitol, voglibose), thizaolidinedione (e.g., rosiglitazone,pioglitazone), insulin analog (e.g., insulin lispro, insulin aspart,insulin glargine), chromium picolinate/biotin, and biological agent(e.g., adiponectin or a fragment comprising the C-terminal globulardomain thereof, or a multimer of adiponectin or said fragment thereof;or an agonist of adiponectin receptor AdipoR1 or AdipoR2, preferablywherein said agonist is orally active). In one aspect of the presentinvention, the pharmaceutical agent is metformin. In one aspect of thepresent invention, the pharmaceutical agent is an agonist to adiponectinreceptor AdipoR1 or AdipoR2, preferably wherein the agonist is orallyactive.

In a combination therapy according to the present invention, the GPR119agonist according to the present invention and the DPP-IV inhibitoraccording to the present invention can be administered simultaneously orat separate intervals. When administered simultaneously the GPR119agonist and the DPP-IV inhibitor can be incorporated into a singlepharmaceutical composition or into separate compositions, e.g., theGPR119 agonist in one composition and the DPP-IV inhibitor in anothercomposition. Each of these compositions may be formulated with commonexcipients, diluents or carriers, and compressed into tablets, orformulated elixirs or solutions; and as sustained relief dosage formsand the like. The GPR119 agonist and DPP-IV inhibitor may beadministered via different routes. For example, the GPR119 agonist maybe administered orally via tablet and the DPP-IV inhibitor may beadministered via inhalation.

When separately administered, therapeutically effective amounts of theGPR119 agonist and the DPP-IV inhibitor according to the presentinvention are administered on a different schedule. One may beadministered before the other as long as the time between the twoadministrations falls within a therapeutically effective interval. Atherapeutically effective interval is a period of time beginning whenone of either (a) the GPR119 agonist or (b) the DPP-IV inhibitor isadministered to a mammal and ending at the limit of the beneficialeffect in the treatment of the combination of (a) and (b).

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier.

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in lowering a blood glucose levelin a subject. In certain embodiments, the blood glucose level is anelevated blood glucose level.

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in lowering a blood glucose levelin a subject, and wherein the amount of the GPR119 agonist alone and theamount of the DPP-IV inhibitor alone are therapeutically ineffective inlowering the blood glucose level in the subject. In certain embodiments,the blood glucose level is an elevated blood glucose level.

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in lowering a blood glucose levelin a subject, and wherein the effect is a synergistic effect. In certainembodiments, the blood glucose level is an elevated blood glucose level.

In one aspect, the present invention relates to a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in lowering a blood glucose levelin a subject, wherein the effect is a synergistic effect, and whereinthe amount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are therapeutically ineffective in lowering the bloodglucose level in the subject. In certain embodiments, the blood glucoselevel is an elevated blood glucose level.

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in increasing a blood GLP-1 levelin a subject.

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in increasing a blood GLP-1 levelin a subject, and wherein the amount of the GPR119 agonist alone and theamount of the DPP-IV inhibitor alone are therapeutically ineffective inincreasing a blood GLP-1 level in the subject.

In one aspect, the present invention features a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in increasing a blood GLP-1 levelin a subject, and wherein the effect is a synergistic effect.

In one aspect, the present invention relates to a pharmaceuticalcomposition comprising or consisting essentially of a combination of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention,together with at least one pharmaceutically acceptable carrier. Thepresent invention also relates to a dosage form of the pharmaceuticalcomposition wherein the GPR119 agonist and the DPP-IV inhibitor are inamounts sufficient to give an effect in increasing a blood GLP-1 levelin a subject, wherein the effect is a synergistic effect, and whereinthe amount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are therapeutically ineffective in increasing a bloodGLP-1 level in the subject.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount to achieve their intended purpose. In some embodiments, apharmaceutical composition of the present invention is understood to beuseful for treating or preventing diabetes and conditions relatedthereto. Diabetes and conditions related thereto are according to thepresent invention. In some embodiments, a pharmaceutical composition ofthe present invention is understood to be useful for treating orpreventing a condition ameliorated by increasing a blood GLP-1 level.Conditions ameliorated by increasing a blood GLP-1 level are accordingto the present invention.

In certain embodiments of the combination therapy of the presentinvention, the amount of GPR119 agonist according to the presentinvention and the amount of DPP-IV inhibitor according to the presentinvention are provided in amounts to give a synergistic effect inlowering a blood glucose level in a subject. In certain embodiments, theblood glucose level is an elevated blood glucose level. Determination ofthe amounts of GPR119 agonist and DPP-IV inhibitor providing asynergistic effect in lowering blood glucose level in a subject is wellwithin the capability of those skilled in the art, especially in lightof the detailed disclosure provided herein. In one embodiment of thecombination therapy of the present invention, the amount of GPR119agonist according to the present invention and the amount of DPP-IVinhibitor according to the present invention are provided in amounts togive a synergistic effect in lowering a blood glucose level in asubject, wherein the amount of the GPR119 agonist alone and the amountof the DPP-IV inhibitor alone are therapeutically ineffective inlowering the blood glucose level in the subject. In certain embodiments,the blood glucose level is an elevated blood glucose level.Determination of the amounts of GPR119 agonist and DPP-IV inhibitorproviding a synergistic effect in lowering blood glucose level in asubject, wherein the amount of the GPR119 agonist alone and the amountof the DPP-IV inhibitor alone are therapeutically ineffective inlowering blood glucose level in the subject, is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

In certain embodiments of the combination therapy of the presentinvention, the amount of GPR119 agonist according to the presentinvention and the amount of DPP-IV inhibitor according to the presentinvention are provided in amounts to give a synergistic effect inincreasing a blood GLP-1 level in a subject. Determination of theamounts of GPR119 agonist and DPP-IV inhibitor providing a synergisticeffect in increasing a blood GLP-1 level in a subject is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein. In one embodiment of thecombination therapy of the present invention, the amount of GPR119agonist according to the present invention and the amount of DPP-IVinhibitor according to the present invention are provided in amounts togive a synergistic effect in increasing a blood GLP-1 level in asubject, wherein the amount of the GPR119 agonist alone and the amountof the DPP-IV inhibitor alone are therapeutically ineffective inincreasing a blood GLP-1 level in the subject. Determination of theamounts of GPR119 agonist and DPP-IV inhibitor providing a synergisticeffect in increasing a blood GLP-1 level in a subject, wherein theamount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are therapeutically ineffective in increasing a bloodGLP-1 level in the subject, is well within the capability of thoseskilled in the art, especially in light of the detailed disclosureprovided herein.

The data obtained from animal studies, including but not limited tostudies using mice, rats, rabbits, pigs, and non-human primates, can beused in formulating a range of dosage for use in humans. In general, oneskilled in the art understands how to extrapolate in vivo data obtainedin an animal model system to another, such as a human. In somecircumstances, these extrapolations may merely be based on the weight ofthe animal model in comparison to another, such as a human; in othercircumstances, these extrapolations are not simply based on weights butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

An exemplary and preferred animal model system is oral glucose tolerancetest (oGTT) in mice (see, Example 1). In this model, by way ofillustration and not limitation, an amount of a GPR119 agonist alone ora DPP-IV inhibitor alone which is therapeutically ineffective is anamount of the GPR119 agonist alone or the DPP-IV inhibitor aloneproducing an Area Under Curve (AUC) inhibition of glycemic excursionless than or equal to about 30%, less than about 25%, less than about20%, less than about 15%, less than about 10%, or less than about 5%,more preferably less than about 25%, less than about 20%, less thanabout 15%, less than about 10%, or less than about 5%. In this model, byway of illustration and not limitation, an amount of a GPR119 agonistalone or a DPP-IV inhibitor alone which is therapeutically ineffectiveis an amount of the GPR119 agonist alone or the DPP-IV inhibitor aloneproducing an Area Under Curve (AUC) inhibition of glycemic excursionabout 0-30%, about 0-25%, about 0-20%, about 0-15%, about 0-10%, orabout 0-5%, more preferably about 0-25%, about 0-20%, about 0-15%, about0-10%, or about 0-5%. In this model, by way of illustration and notlimitation, a therapeutically effective amount of a combination of aGPR119 agonist and a DPP-IV inhibitor in accordance with the presentinvention is an amount of the combination producing an Area Under Curve(AUC) inhibition of glycemic excursion greater than about 30%, greaterthan about 35%, greater than about 40%, greater than about 45%, greaterthan about 50%, greater than about 55%, greater than about 60%, greaterthan about 65%, greater than about 70%, greater than about 75%, greaterthan about 80%, greater than about 85%, greater than about 90%, orgreater than about 95%, more preferably greater than about 35%, greaterthan about 40%, greater than about 45%, greater than about 50%, greaterthan about 55%, greater than about 60%, greater than about 65%, greaterthan about 70%, or greater than about 75%, greater than about 80%,greater than about 85%, greater than about 90%, or greater than about95%.

Dosage amount and interval may be adjusted in order to provide asynergistic effect in lowering a blood glucose level in the subject inaccordance with the present invention or to provide a synergistic effectin increasing a blood GLP-1 level in the subject in accordance with thepresent invention. In certain embodiments, the blood glucose level is anelevated blood glucose level. It will be appreciated that the exactdosage of a GPR119 agonist or DPP-IV inhibitor in accordance with thepresent invention will vary depending on the combination of the GPR119agonist and DPP-IV inhibitor, its potency, the mode of administration,the age and weight of the patient and the severity of the condition tobe treated. The exact formulation, route of administration and dosagecan be chosen by the individual physician in view of the patient'scondition. By way of illustration and not limitation, an amount ofGPR119 agonist or DPP-IV inhibitor providing a synergistic effect inlowering a blood glucose level in the subject in accordance with thepresent invention or providing a synergistic effect in increasing ablood GLP-1 level in the subject in accordance with the presentinvention is less than about 0.001 mg/kg body weight, less than about0.005 mg/kg body weight, less than about 0.01 mg/kg body weight, lessthan about 0.05 mg/kg body weight, less than about 0.1 mg/kg bodyweight, less than about 0.5 mg/kg body weight, less than about 1 mg/kgbody weight, less than about 5 mg/kg body weight, less than about 10mg/kg body weight, less than about 50 mg/kg body weight, or less thanabout 100 mg/kg body weight. In certain embodiments, the blood glucoselevel is an elevated blood glucose level. In some embodiments, an amountof GPR119 agonist or DPP-IV inhibitor providing a synergistic effect inlowering a blood glucose level in the subject in accordance with thepresent invention or providing a synergistic effect in increasing ablood GLP-1 level in the subject in accordance with the presentinvention is less than about 0.001-100 mg/kg body weight, less thanabout 0.001-50 mg/kg body weight, less than about 0.001-10 mg/kg bodyweight, less than about 0.001-5 mg/kg body weight, less than about0.001-1 mg/kg body weight, less than about 0.001 to 0.5 mg/kg bodyweight, less than about 0.001-0.1 mg/kg body weight, less than about0.001-0.05 mg/kg body weight, less than about 0.001-0.01 mg/kg bodyweight, or less than about 0.001-0.005 mg/kg body weight. In certainembodiments, the blood glucose level is an elevated blood glucose level.In some embodiments, an amount of GPR119 agonist or DPP-IV inhibitorproviding a synergistic effect in lowering a blood glucose level in thesubject in accordance with the present invention or providing asynergistic effect in increasing a blood GLP-1 level in the subject inaccordance with the present invention is about 0.001-100 mg/kg bodyweight, about 0.001-50 mg/kg body weight, about 0.001-10 mg/kg bodyweight, about 0.001-5 mg/kg body weight, about 0.001 to 1 mg/kg bodyweight, about 0.001-0.5 mg/kg body weight, about 0.001-0.1 mg/kg bodyweight, about 0.001-0.05 mg/kg body weight, about 0.001-0.01 mg/kg bodyweight, or about 0.001-0.005 mg/kg body weight. In certain embodiments,the blood glucose level is an elevated blood glucose level.

An additional exemplary and preferred animal model system is increase ofa blood GLP-1 level after glucose challenge in mice (see, Example 3).

Dosage amount and interval may be adjusted individually to provideplasma levels of GPR119 agonist according to the present invention andDPP-IV inhibitor according to the present invention which provide asynergistic effect in lowering a blood glucose level in the subjectaccording to the present invention or provide a synergistic effect inincreasing a blood GLP-1 level in the subject according to the presentinvention. In certain embodiments, the blood glucose level is anelevated blood glucose level. Dosage intervals can also be determinedusing the value for a selected range of GPR119 agonist concentration orthe value for a selected range of DPP-IV inhibitor concentrationproviding a synergistic effect in lowering a blood glucose level in thesubject according to the present invention or providing a synergisticeffect in increasing a blood GLP-1 level in the subject according to thepresent invention. In certain embodiments, the blood glucose level is anelevated blood glucose level. GPR119 agonist and DPP-IV inhibitor shouldbe administered using a regimen that maintains plasma levels within theselected range of GPR119 agonist concentration and DPP-IV inhibitorconcentration, respectively, for 10-90% of the time, preferably between30-99% of the time, and most preferably between 50-90% of the time. Incases of local administration or selective uptake, the range of GPR119agonist concentration or the range of DPP-IV inhibitor concentrationproviding a synergistic effect in lowering a blood glucose level in thesubject according to the present invention or providing a synergisticeffect in increasing a blood GLP-1 level in the subject according to thepresent invention may not be related to plasma concentration. In certainembodiments, the blood glucose level is an elevated blood glucose level.

The amount of composition admininistered will, of course, be dependenton the subject being treated, on the subject's weight, the severity ofthe affliction, the manner of administration, and the judgement of theprescribing physician.

In one aspect, the present invention accordingly features a method oftreating or preventing diabetes or a condition related theretocomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention.

In one aspect, the present invention relates to a method of treating orpreventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in lowering a blood glucose level in thesubject. In certain embodiments, the blood glucose level is an elevatedblood glucose level.

In one aspect, the present invention relates to a method of treating orpreventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said mehod wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in lowering a blood glucose level in thesubject, and wherein the amount of the GPR119 agonist alone and theamount of the DPP-IV inhibitor alone are therapeutically ineffective inlowering the blood glucose level in the subject. In certain embodiments,the blood glucose level is an elevated blood glucose level.

In one aspect, the present invention relates to a method of treating orpreventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in lowering a blood glucose level in thesubject, and wherein the effect is a synergistic effect. In certainembodiments, the blood glucose level is an elevated blood glucose level.

In one aspect, the present invention relates to a method of treating orpreventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and anamount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in lowering a blood glucose level in thesubject, wherein the effect is a synergistic effect, and wherein theamount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are therapeutically ineffective in lowering the bloodglucose level in the subject. In certain embodiments, the blood glucoselevel is an elevated blood glucose level.

A combination therapy of the present invention is useful in treating orpreventing diabetes or a condition related thereto in a mammal,including and most preferably in a human. In some embodiments, diabetesis Type 1 diabetes. In some preferred embodiments, diabetes is Type 2diabetes. A condition related to diabetes includes, but is not limitedto, hyperglycemia, impaired glucose tolerance, insulin resistance,pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency,glucosuria, metabolic acidosis, cataracts, diabetic nephropathy,diabetic neuropathy, diabetic retinopathy, diabetic coronary arterydisease, diabetic cerebrovascular disease, diabetic peripheral vasculardisease, metabolic syndrome, hyperlipidemia, atherosclerosis, stroke,hypertension, and obesity. It is understood that conditions related todiabetes can be included in embodiments individually or in anycombination.

In one aspect, the present invention accordingly features a method oftreating or preventing a condition ameliorated by increasing a bloodGLP-1 level comprising administering to a subject in need thereof atherapeutically effective amount of a composition comprising orconsisting essentially of an amount of a GPR119 agonist according to thepresent invention and an amount of a DPP-IV inhibitor according to thepresent invention.

In one aspect, the present invention relates to a method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in increasing a blood GLP-1 level in thesubject.

In one aspect, the present invention relates to a method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in increasing a blood GLP-1 level in thesubject, and wherein the amount of the GPR119 agonist alone and theamount of the DPP-IV inhibitor alone are therapeutically ineffective inincreasing a blood GLP-1 level in the subject.

In one aspect, the present invention relates to a method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in increasing a blood GLP-1 level in thesubject, and wherein the effect is a synergistic effect.

In one aspect, the present invention relates to a method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in increasing a blood GLP-1 level in thesubject, wherein the effect is a synergistic effect, and wherein theamount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are therapeutically ineffective in increasing a bloodGLP-1 level in the subject.

A combination therapy of the present invention is useful in treating orpreventing a condition ameliorated by increasing a blood GLP-1 level ina mammal, including and most preferably in a human. A conditionameliorated by increasing a blood GLP-1 level includes, but is notlimited to, diabetes, a condition related to diabetes, myocardialinfarction, learning impairment, memory impairment, and aneurodegenerative disorder, wherein a condition related to diabetesincludes, but is not limited to, hyperglycemia, impaired glucosetolerance, insulin resistance, pancreatic beta-cell insufficiency,enteroendocrine cell insufficiency, glucosuria, metabolic acidosis,cataracts, diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, diabetic coronary artery disease, diabetic cerebrovasculardisease, diabetic peripheral vascular disease, metabolic syndrome,hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity,wherein a neurodegenerative disorder includes, but is not limited to,excitotoxic brain damage caused by severe epileptic seizures,Alzheimer's disease, Parkinson's disease, Huntington's disease,prion-associated disease, motor-neuron disease, traumatic brain injury,spinal cord injury, and peripheral neuropathy. In some embodiments,diabetes is Type I diabetes. In some preferred embodiments, diabetes isType 2 diabetes. It is understood that conditions ameliorated byincreasing a blood GLP-1 level can be included in embodimentsindividually or in any combination.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The foregoing detailed description is given forclearness of understanding only, and no unnecessary limitation should beunderstood therefrom, as modifications within the scope of the inventionmay become apparent to those skilled in the art.

The inventions described in this application were made by ArenaPharmaceuticals, Inc as a result of activities undertaken within thescope of a Dec. 20, 2004 joint research agreement between Ortho-McNeilPharmaceutical, Inc. and Arena Pharmaceuticals, Inc.

Throughout this application, various publications, patents and patentapplications are cited. The disclosures of these publications, patentsand patent applications referenced in this application are hereinincorporated by reference in their entirety into the present disclosure.Citation herein by Applicant of a publication, patent, or patentapplication is not an admission by Applicant of said publication,patent, or patent application as prior art.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples are to be construedas merely illustrative, and not limitations of the preceding disclosurein any way whatsoever. Those skilled in the art will promptly recognizeappropriate variations from the procedures.

Example 1 Synergistic Effect of GPR119 Agonist and DPP-IV Inhibitor inLowering an Elevated Blood Glucose Level in Oral Glucose Tolerance Test(OGTT) in Mice

Oral glucose tolerance test (OGTT) in mice was carried out as describedhere. Overnight fasted mice (n=6 mice per treatment) were administeredvia oral gavage with vehicle (PET), a GPR119 agonist (AR231453) at 1 mkg(milligram compound per kilogram of body weight), a DPP-IV inhibitor(AR247810) at 0.1 mkg, or a combination of the GPR119 agonist (1 mkg)and the DPP-IV inhibitor (0.1 mkg). Thirty minutes later, a glucosebolus (3 gram/kg) was then delivered per orally. Plasma glucose levelswere determined at the indicated time points over a two hour periodusing blood (˜5 μl) collected from tail nick and a glucose meter.Glycemic excursion curve was graphed based on data from 6 mice and givenin mean values ± SEM (FIG. 1A). Area Under Curve (AUC) of the glycemicexcursion was calculated for each mouse and AUC inhibition (%) wasreported in FIG. 1B.

In this Example, GPR119 agonist given at 1 mkg alone, or DPP-IVinhibitor given at 0.1 mkg alone produced an AUC inhibition of glycemicexcursion less than 15-20% in this mouse model, which is regarded astherapeutically ineffective for the long term glycemic control indiabetic patients. On the other hand, the combination of both compoundsat their therapeutically ineffective dose (0.1 mkg for the DPP-IVinhibitor, and 1 mkg for the GPR119 agonist in this Example) produced anAUC inhibition over 60%. Typically, a therapeutically effective dosewould create an AUC inhibition above 30% in this mouse model study, suchas that observed for the incretin mimetic exendin-4 at ˜60%.

Both the DPP-IV inhibitor and the GPR119 agonist alone can produce aneffective therapeutic response (at around 40% AUC inhibition) in thistype of mouse model study, but only at significantly higher doses (FIG.1C and FIG. 1D, respectively).

Example 2 Combination of GPR119 Agonist and DPP-IV Inhibitor forTreating or Preventing Diabetes and Conditions Related Thereto

A GPR119 agonist in accordance with the present invention is selected. ADPP-IV inhibitor in accordance with the present invention is selected.

Titration of the GPR119 agonist with respect to percent inhibition ofArea Under Curve (AUC) in mouse oral glucose tolerance test (oGTT) isdetermined across a dose range from about 0.01 mkg (milligram compoundper kilogram of body weight) to about 100 mkg. See Example 1. A dose ofthe GPR119 agonist producing an AUC inhibition of glycemic excursion ofabout 15-20% is chosen. Typically, a dose of GPR119 agonist producing anAUC inhibition 30% or less is therapeutically ineffective in this mousemodel.

Titration of the DPP-IV inhibitor with respect to percent inhibition ofArea Under Curve (AUC) in mouse oral glucose tolerance test (OGTT) isdetermined across a dose range from about 0.01 mkg (milligram compoundper kilogram of body weight) to about 100 mkg. See Example 1. A dose ofthe DPP-IV inhibitor producing an AUC inhibition of glycemic excursionof about 15-20% is chosen. Typically, a dose of DPP-IV inhibitorproducing an AUC inhibition 30% or less is therapeutically ineffectivein this mouse model.

The AUC inhibition of glycemic excursion produced by the combination ofthe chosen dose of the GPR119 agonist and the chosen dose of the DPP-IVinhibitor is determined in mouse oGTT assay. Therapeutic efficacy of thecombination of the GPR119 agonist and the DPP-IV inhibitor isdetermined. Typically, an amount of the combination producing an AUCinhibition above 30% is therapeutically effective in this mouse model.Synergism between the GPR119 agonist and the DPP-IV inhibitor isdetermined.

Data obtained from this mouse model can be used to formulate a range ofdosage for use in humans. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in an animal model system toanother, such as a human. A combination of GPR119 agonist and DPP-IVinhibitor in accordance with the present invention is useful in treatingor preventing diabetes and conditions related thereto.

It is understood that the foregoing is intended to be illustrative andnot limiting.

Example 3 Synergistic Effect of GPR119 Agonist and DPP-IV Inhibitor inIncreasing a Blood GLP-1 Level After Glucose Challenge in Mice

C57blk/6 male mice (8 weeks of age) were fasted for 18 hours, andrandomly assigned into twelve groups with n=6 for each group. Mice wereadministered per orally with vehicle (PET), GPR119 agonist (10 mg/kg)DPP-IV inhibitor (1 mg/kg), or a combination of GPR119 agonist andDPP-IV inhibitor, as indicated. The GPR119 agonist (AR231453) and theDPP-IV inhibitor (AR247810) used here are identical to those used inExample 1. Thirty minutes after treatment, a glucose bolus at 3 g/kgwere delivered per orally, and plasma were collected at 0 minute (noglucose bolus), and at 2 minutes and 5 minutes after glucose bolus.Plasma GLP-1 levels were determined by using a GLP-1 ELISA kit purchasedfrom Linco Research Laboratory [Glucagon-Like Peptide-1 (Active) ELISAkit, Catalog #EGLP-35K].

Administration of a GPR119 agonist together with a DPP-IV inhibitor wasfound to produce a synergistic effect in increasing a blood GLP-1 level.See FIG. 2.

Example 4 Melanophor Assay for GPR119 Agonist Activity

Melanophores are maintained in culture as reported by Potenza et al[Pigment Cell Research (1992) 5:372-378] and transfected with anexpression vector encoding a GPR119 receptor (GPR119; e.g., humanGPR119, GenBank® Accession No. AAP72125 and alleles thereof) usingelectroporation. Following electroporation, the transfected cells areplated into 96 well plates for the assay. The cells are then allowed togrow for 48 hours in order to both recover from the electroporationprocedure and attain maximal receptor expression levels.

On the assay day, the growth medium on the cells is replaced withserum-free buffer containing 10 nM melatonin. The melatonin acts via anendogenous Gi-coupled GPCR in the melanophores to lower intracellularcAMP levels. In response to lowered cAMP levels, the melanophorestranslocate their pigment to the center of the cell. The net effect ofthis is a significant decrease in the absorbance reading of the cellmonolayer in the well, measured at 600-650 nM.

After a 1-hour incubation in melatonin, the cells become completelypigment-aggregated. At this point a baseline absorbance reading iscollected. Serial dilutions of test compounds are then added to theplate, and compounds having GPR119 agonist activity produce increases inintracellular cAMP levels. In response to these increased cAMP levels,the melanophores translocate their pigment back into the cell periphery.After one hour, stimulated cells are fully pigment-dispersed. The cellmonolayer in the dispersed state absorbs much more light in the 600-650nm range. The measured increase in absorbance compared to the baselinereading allows one to quantitate the degree of receptor stimulation andplot a dose-response curve.

Materials and methods relating to melanophore assay are found in U.S.Pat. Nos. 5,462,856 and 6,051,386, the disclosure of each of which isherein incorporated by reference in its entirety.

Other assays for identifying a compound as a GPR119 agonist will bereadily apparent to the skilled artisan (see, e.g., Example 7, infra).

Example 5

Full-Length Cloning of Endogenous Human GPR119

Polynucleotide encoding endogenous human GPR119 was cloned by PCR usingthe GPR119 specific primers: 5′-GTCCTGCCACTTCGAGACATGG-3′; (SEQ ID NO: 3sense, ATG as initiation codon) 5′-GAAACTTCTCTGCCCTTACCGTC-3′; (SEQ IDNO: 4 antisense, 3′ of stop codon)and human genomic DNA as template. TaqPlus Precision™ DNA polymerase(Stratagene) was used for amplification by the following cycle with step2 to step 4 repeated 35 times: 94° C., 3 minutes; 94° C., 1 minute; 58°C., 1 minute; 72° C., 2 minutes; 72° C., 10 minutes. A 1.0 Kb PCRfragment of predicted size was isolated and cloned into the pCRII-TOPO™vector (Invitrogen) and completely sequenced using the T7 DNA sequenasekit (Amersham). See, SEQ ID NO:1 for nucleic acid sequence and SEQ IDNO:2 for the deduced amino acid sequence.

Example 6

Receptor Expression

Although a variety of cells are available to the art for the expressionof G protein-coupled receptors, it is most preferred that mammaliancells or melanophores be utilized. The following are illustrative; thoseof ordinary skill in the art are credited with the ability to determinethose techniques that are preferentially beneficial for the needs of theartisan. See, e.g., Example 4, supra, as it relates to melanophores.

a. Transient Transfection

On day one, 6×10⁶/10 cm dish of 293 cells are plated out. On day two,two reaction tubes are prepared (the proportions to follow for each tubeare per plate): tube A is prepared by mixing 4 μg DNA (e.g., pCMVvector; pCMV vector with receptor cDNA, etc.) in 0.5 ml serum free DMEM(Gibco BRL); tube B is prepared by mixing 24 μl lipofectamine (GibcoBRL) in 0.5 ml serum free DMEM. Tubes A and B are admixed by inversions(several times), followed by incubation at room temperature for 30-45min. The admixture is referred to as the “transfection mixture”. Plated293 cells are washed with 1× PBS, followed by addition of 5 ml serumfree DMEM. 1 ml of the transfection mixture is added to the cells,followed by incubation for 4 hrs at 37° C./5% CO₂. The transfectionmixture is removed by aspiration, followed by the addition of 10 ml ofDMEM/10% Fetal Bovine Serum. Cells are incubated at 37° C./5% CO₂. After48 hr incubation, cells are harvested and utilized for analysis.

b. Stable Cell Lines

Approximately 12×10⁶ 293 cells are plated on a 15 cm tissue cultureplate. Grown in DME High Glucose Medium containing ten percent fetalbovine serum and one percent sodium pyruvate, L-glutamine, andantibiotics. Twenty-four hours following plating of 293 cells (or to-80% confluency), the cells are transfected using 12 μg of DNA (e.g.,pCMV-neo^(r) vector with receptor cDNA). The 12 kg of DNA is combinedwith 60 μl of lipofectamine and 2 ml of DME High Glucose Medium withoutserum. The medium is aspirated from the plates and the cells are washedonce with medium without serum. The DNA, lipofectamine, and mediummixture are added to the plate along with 10 ml of medium without serum.Following incubation at 37° C. for four to five hours, the medium isaspirated and 25 ml of medium containing serum is added. Twenty-fourhours following transfection, the medium is aspirated again, and freshmedium with serum is added. Forty-eight hours following transfection,the medium is aspirated and medium with serum is added containinggeneticin (G418 drug) at a final concentration of approximately 12×10⁶293 cells are plated on a 15 cm tissue culture plate. Grown in DME HighGlucose Medium containing ten percent fetal bovine serum and one percentsodium pyruvate, L-glutamine, and antibiotics. Twenty-four hoursfollowing plating of 293 cells (or to ˜80% confluency), the cells aretransfected using 12 μg of DNA (e.g., pCMV vector with receptor cDNA).The 12 μg of DNA is combined with 60 μl of lipofectamine and 2 ml of DMEHigh Glucose Medium without serum. The medium is aspirated from theplates and the cells are washed once with medium without serum. The DNA,lipofectamine, and medium mixture are added to the plate along with 10ml of medium without serum. Following incubation at 37° C. for four tofive hours, the medium is aspirated and 25 ml of medium containing serumis added. Twenty-four hours following transfection, the medium isaspirated again, and fresh medium with serum is added. Forty-eight hoursfollowing transfection, the medium is aspirated and medium with serum isadded containing geneticin (G418 drug) at a final concentration of 500μg/ml. The transfected cells now undergo selection for positivelytransfected cells containing the G418 resistance gene. The medium isreplaced every four to five days as selection occurs. During selection,cells are grown to create stable pools, or split for stable clonalselection.

Example 7

Assays for Screening Candidate Compounds as GPR119 Agonists

A variety of approaches are available for screening candidate compoundsas GPR119 agonists. The following are illustrative; those of ordinaryskill in the art are credited with the ability to determine thosetechniques that are preferentially beneficial for the needs of theartisan. Assays for screening compounds as agonists of a Gprotein-coupled receptor are well known to the skilled artisan (see,e.g., International Application WO 02/42461).

1. Membrane Binding Assays: [³⁵S]GTPγS Assay

When a G protein-coupled receptor is in its active state, either as aresult of ligand binding or constitutive activation, the receptorcouples to a G protein and stimulates the release of GDP and subsequentbinding of GTP to the G protein. The alpha subunit of the Gprotein-receptor complex acts as a GTPase and slowly hydrolyzes the GTPto GDP, at which point the receptor normally is deactivated. Activatedreceptors continue to exchange GDP for GTP. The non-hydrolyzable GTPanalog, [³⁵S]GTPγS, can be utilized to demonstrate enhanced binding of[³⁵S]GTPγS to membranes expressing activated receptors. The advantage ofusing [³⁵S]GTPγS binding to measure activation is that: (a) it isgenerically applicable to all G protein-coupled receptors; (b) it isproximal at the membrane surface making it less likely to pick-upmolecules which affect the intracellular cascade.

The assay utilizes the ability of G protein coupled receptors tostimulate [³⁵S]GTPγS binding to membranes expressing the relevantreceptors. The assay is generic and has application to drug discovery atall G protein-coupled receptors.

Membrane Preparation

In some embodiments, membranes comprising a G protein-coupled receptorof the invention and for use in the identification of candidatecompounds as, e.g., agonists of the receptor, are preferably prepared asfollows:

a. Materials

“Membrane Scrape Buffer” is comprised of 20 mM HEPES and 10 mM EDTA, pH7.4; “Membrane Wash Buffer” is comprised of 20 mM HEPES and 0.1 mM EDTA,pH 7.4; “Binding Buffer” is comprised of 20 mM HEPES, 100 mM NaCl, and10 mM MgCl₂, pH 7.4.

b. Procedure

All materials will be kept on ice throughout the procedure. Firstly, themedia will be aspirated from a confluent monolayer of cells, followed byrinse with 10 ml cold PBS, followed by aspiration. Thereafter, 5 ml ofMembrane Scrape Buffer will be added to scrape cells; this will befollowed by transfer of cellular extract into 50 ml centrifuge tubes(centrifuged at 20,000 rpm for 17 minutes at 4° C.). Thereafter, thesupernatant will be aspirated and the pellet will be resuspended in 30ml Membrane Wash Buffer followed by centrifuge at 20,000 rpm for 17minutes at 4° C.. The supernatant will then be aspirated and the pelletresuspended in Binding Buffer. This will then be homogenized using aBrinkman Polytron™ homogenizer (15-20 second bursts until the allmaterial is in suspension). This is referred to herein as “MembraneProtein”.

Bradford Protein Assay

Following the homogenization, protein concentration of the membraneswill be determined using the Bradford Protein Assay (protein can bediluted to about 1.5 mg/ml, aliquoted and frozen (−80° C.) for lateruse; when frozen, protocol for use will be as follows: on the day of theassay, frozen Membrane Protein is thawed at room temperature, followedby vortex and then homogenized with a Polytron at about 12×1,000 rpm forabout 5-10 seconds; it is noted that for multiple preparations, thehomogenizer should be thoroughly cleaned between homogenization ofdifferent preparations).

a. Materials

Binding Buffer (as per above); Bradford Dye Reagent; Bradford ProteinStandard will be utilized, following manufacturer instructions (Biorad,cat. no.500-0006).

b. Procedure Duplicate tubes will be prepared, one including themembrane, and one as a control “blank”. Each contained 800μl BindingBuffer. Thereafter, 10 μl of Bradford Protein Standard (1 mg/ml) will beadded to each tube, and 10 μl of membrane Protein will then be added tojust one tube (not the blank). Thereafter, 200 μl of Bradford DyeReagent will be added to each tube, followed by vortex of each. Afterfive (5) minutes, the tubes will be re-vortexed and the material thereinwill be transferred to cuvettes. The cuvettes will then be read using aCECIL 3041 spectrophotometer, at wavelength 595.

Identification Assay

a. Materials

GDP Buffer consists of 37.5 ml Binding Buffer and 2 mg GDP (Sigma, cat.no. G-7127), followed by a series of dilutions in Binding Buffer toobtain 0.2 μM GDP (final concentration of GDP in each well was 0.1 μMGDP); each well comprising a candidate compound, has a final volume of200 μl consisting of 100 μl GDP Buffer (final concentration, 0.1 μMGDP), 50 μl Membrane Protein in Binding Buffer, and 50 μl [³⁵S]GTPγS(0.6 nM) in Binding Buffer (2.5 μl [³⁵S]GTPγS per 10 ml Binding Buffer).

b. Procedure

Candidate compounds will be preferably screened using a 96-well plateformat (these can be frozen at −80° C.). Membrane Protein (or membraneswith expression vector excluding the Target GPCR, as control), will behomogenized briefly until in suspension. Protein concentration will thenbe determined using the Bradford Protein Assay set forth above. MembraneProtein (and control) will then be diluted to 0.25 mg/ml in BindingBuffer (final assay concentration, 12.5 μg/well). Thereafter, 100 μl GDPBuffer was added to each well of a Wallac Scintistrip™ (Wallac). A 5 μlpin-tool will then be used to transfer 5 μl of a candidate compound intosuch well (i.e., 5 μl in total assay volume of 200 μl is a 1:40 ratiosuch that the final screening concentration of the candidate compound is10 μM). Again, to avoid contamination, after each transfer step the pintool should be rinsed in three reservoirs comprising water (1×), ethanol(1×) and water (2×)—excess liquid should be shaken from the tool aftereach rinse and dried with paper and kimwipes. Thereafter, 50 μl ofMembrane Protein will be added to each well (a control well comprisingmembranes without the Target GPCR was also utilized), and pre-incubatedfor 5-10 minutes at room temperature. Thereafter, 50 μl of [³⁵S]GTPγS(0.6 nM) in Binding Buffer will be added to each well, followed byincubation on a shaker for 60 minutes at room temperature (again, inthis example, plates were covered with foil). The assay will then bestopped by spinning of the plates at 4000 RPM for 15 minutes at 22° C..The plates will then be aspirated with an 8 channel manifold and sealedwith plate covers. The plates will then be read on a Wallac 1450 usingsetting “Prot. #37” (as per manufacturer's instructions).

2. Adenylyl Cyclase Assay

A Flash Plate™ Adenylyl Cyclase kit (New England Nuclear; Cat. No.SMP004A) designed for cell-based assays can be modified for use withcrude plasma membranes. The Flash Plate wells can contain a scintillantcoating which also contains a specific antibody recognizing cAMP. ThecAMP generated in the wells can be quantitated by a direct competitionfor binding of radioactive cAMP tracer to the cAMP antibody. Thefollowing serves as a brief protocol for the measurement of changes incAMP levels in whole cells that express the receptors.

In certain embodiments, a modified Flash Plate™ Adenylyl Cyclase kit(New England Nuclear; Cat. No. SMP004A) is utilized for identificationof candidate compounds as, e.g., GPR119 agonists in accordance with thefollowing protocol.

Cells transfected with a G protein-coupled receptor of the invention areharvested approximately three days after transfection. Membranes areprepared by homogenization of suspended cells in buffer containing 20 mMHEPES, pH 7.4 and 1 mM MgCl₂. Homogenization is performed on ice using aBrinkman Polytron™ for approximately 10 seconds. The resultinghomogenate is centrifuged at 49,000×g for 15 minutes at 4° C. Theresulting pellet is then resuspended in buffer containing 20 mM HEPES,pH 7.4 and 0.1 mM EDTA, homogenized for 10 seconds, followed bycentrifugation at 49,000×g for 15 minutes at 4° C. The resulting pelletis then stored at −80° C. until utilized. On the day of directidentification screening, the membrane pellet is slowly thawed at roomtemperature, resuspended in buffer containing 20 mM HEPES, pH 7.4 and 10mM MgCl₂, to yield a final protein concentration of 0.60 mg/ml (theresuspended membranes are placed on ice until use).

cAMP standards and Detection Buffer (comprising 2 μCi of tracer{[¹²⁵I]cAMP (100 μl) to 11 ml Detection Buffer] are prepared andmaintained in accordance with the manufacturer's instructions. AssayBuffer was prepared fresh for screening and contained 20mM HEPES, pH7.4, 10 mM MgCl₂, 20 mM phospocreatine (Sigma), 0.1 units/ml creatinephosphokinase (Sigma), 50 μM GTP (Sigma), and 0.2 mM ATP (Sigma); AssayBuffer was then stored on ice until utilized.

Candidate compounds are added, preferably, to e.g. 96-well plate wells(3 μl/well; 12 μM final assay concentration), together with 40 μlMembrane Protein (30 μg/well) and 50 μl of Assay Buffer. This admixturewas then incubated for 30 minutes at room temperature, with gentleshaking.

Following the incubation, 100 μl of Detection Buffer is added to eachwell, followed by incubation for 2-24 hours. Plates are then counted ina Wallac MicroBeta™ plate reader using “Prot. #31” (as permanufacturer's instructions).

3. CRE-Luc Reporter Assay

293 and 293T cells are plated-out on 96 well plates at a density of2×10⁴ cells per well and were transfected using Lipofectamine Reagent(BRL) the following day according to manufacturer instructions. ADNA/lipid mixture is prepared for each 6-well transfection as follows:260 ng of plasmid DNA in 100 μl of DMEM is gently mixed with 2 μl oflipid in 100 μl of DMEM (the 260 ng of plasmid DNA consists of 200 ng ofa 8× CRE-Luc reporter plasmid, 50 ng of pCMV comprising a Gprotein-coupled receptor of the invention or pCMV alone, and 10 ng of aGPRS expression plasmid [GPRS in pcDNA3 (Invitrogen)]. The 8× CRE-Lucreporter plasmid was prepared as follows: vector SRIF-β-gal was obtainedby cloning the rat somatostatin promoter (−71/+51) at BgIV-HindIII sitein the pβgal-Basic Vector (Clontech). Eight (8) copies of cAMP responseelement were obtained by PCR from an adenovirus template AdpCF126CCRE8[see, Suzuki et al., Hum Gene Ther (1996) 7:1883-1893; the disclosure ofwhich is herein incorporated by reference in its entirety) and clonedinto the SRIF-β-gal vector at the Kpn-BgIV site, resulting in the8×CRE-β-gal reporter vector. The 8×CRE-Luc reporter plasmid wasgenerated by replacing the beta-galactosidase gene in the 8×CRE-β-galreporter vector with the luciferase gene obtained from the pGL3-basicvector (Promega) at the HindIII-BamHI site. Following 30 min. incubationat room temperature, the DNA/lipid mixture is diluted with 400 μl ofDMEM and 100 μl of the diluted mixture is added to each well. 100 μl ofDMEM with 10% FCS are added to each well after a 4 hr incubation in acell culture incubator. The following day the transfected cells arechanged with 200 μl/well of DMEM with 10% FCS. Eight (8) hours later,the wells are changed to 100 μl/well of DMEM without phenol red, afterone wash with PBS. Luciferase activity is measured the next day usingthe LucLite™ reporter gene assay kit (Packard) following manufacturerinstructions and read on a 1450 MicroBeta™ scintillation andluminescence counter (Wallac).

Example 8

Radiolabeled Compound

In certain embodiments, a compound known to be a ligand of a Gprotein-coupled receptor of the invention is radiolabeled. Aradiolabeled compound as described herein can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radiolabeled knownligand to the receptor, by its ability to reduce formation of thecomplex between the radiolabeled known ligand and the receptor. Suitableradionuclides that may be incorporated in compounds of the presentinvention include but are not limited to ³H (also written as T), ¹¹C,¹⁴C, ¹⁸F, ¹²⁵I, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ¹⁵O, ¹³N, ³⁵Sand ⁷⁷Br. Compounds that incorporate ³H, ¹⁴C, ¹²⁵I, ¹³¹I, ³⁵S or ⁸²Brwill generally be most useful.

It is understood that a “radiolabelled” compound” is a compound that hasincorporated at least one radionuclide. In some embodiments, theradionuclide is selected from the group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵Sand ⁸²Br. In some embodiments, the radionuclide ³H or ¹⁴C. Moreover, itshould be understood that all of the atoms represented in the compoundsknown to be ligands of a G protein-coupled receptor of the invention canbe either the most commonly occurring isotope of such atoms or the morescarce radioisotope or nonradioactive isotope.

Synthetic methods for incorporating radioisotopes into organic compoundsincluding those applicable to those compounds known to be ligands of a Gprotein-coupled receptor of the invention are well known in the art andinclude incorporating activity levels of tritium into target moleculesinclude: A. Catalytic Reduction with Tritium Gas—This procedure normallyyields high specific activity products and requires halogenated orunsaturated precursors. B. Reduction with Sodium Borohydride [³H]—Thisprocedure is rather inexpensive and requires precursors containingreducible functional groups such as aldehydes, ketones, lactones,esters, and the like. C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offers products at almost theoretical specificactivities. It also requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like. D.Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst. E. N-Methylation using Methyl Iodide[³H]—This procedure is usually employed to prepare O-methyl or N-methyl(³H) products by treating appropriate precursors with high specificactivity methyl iodide (³H). This method in general allows for highspecific activity, such as about 80-87 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include: A. Sandmeyer and like reactions—This proceduretransforms an aryl or heteroaryl amine into a diazonium salt, such as atetrafluoroborate salt, and subsequently to ¹²⁵I labelled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, D.-G. andco-workers in J Org. Chem. 2002, 67, 943-948. B. Ortho ¹²⁵Iodination ofphenols—This procedure allows for the incorporation of ¹²⁵I at the orthoposition of a phenol as reported by Collier, T. L. and co-workers in J.Labelled Compd Radiopharm. 1999, 42, S264-S266. C. Aryl and heteroarylbromide exchange with ¹²⁵—This method is generally a two step process.The first step is the conversion of the aryl or heteroaryl bromide tothe corresponding tri-alkyltin intermediate using for example, a Pdcatalyzed reaction [i.e. Pd(Ph₃P)₄] or through an aryl or heteroaryllithium, in the presence of a tri-alkyltinhalide or hexaalkylditin[e.g., (CH₃)₃SnSn(CH₃)₃]. A represented procedure was reported by Bas,M.-D. and co-workers in J. Labelled Compd Radiopharm. 2001, 44,S280-S282.

The foregoing techniques are intended to be illustrative and notlimiting. Other techniques for radiolabeling a compound known to be aligand of a G protein-coupled receptor of the invention are well knownto the skilled artisan.

Example 9

Receptor Binding Assay

A test compound can be evaluated for its ability to reduce formation ofthe complex between a compound known to be a ligand of a Gprotein-coupled receptor of the invention and the receptor. In certainembodiments, the known ligand is radiolabeled. The radiolabeled knownligand can be used in a screening assay to identify/evaluate compounds.In general terms, a newly synthesized or identified compound (i.e., testcompound) can be evaluated for its ability to reduce binding of theradiolabeled known ligand to the receptor, by its ability to reduceformation of the complex between the radiolabeled known ligand and thereceptor.

Assay Protocol for Detecting the Complex Between a Compound Known to bea Ligand of a G Protein-Coupled Receptor of the Invention and theReceptor

A. Preparation of the Receptor

293 cells are transiently transfected with 10 ug expression vectorcomprising a polynucleotide encoding a G protein-coupled receptor of theinvention using 60 ul Lipofectamine (per 15-cm dish). The transientlytransfected cells are grown in the dish for 24 hours (75% confluency)with a media change and removed with 10 ml/dish of Hepes-EDTA buffer (20 mM Hepes+10 mM EDTA, pH 7.4). The cells are then centrifuged in aBeckman Coulter centrifuge for 20 minutes, 17,000 rpm (JA-25.50 rotor).Subsequently, the pellet is resuspended in 20 mM Hepes+1 mM EDTA, pH 7.4and homogenized with a 50-ml Dounce homogenizer and again centrifuged.After removing the supernatant, the pellets are stored at −80° C., untilused in binding assay. When used in the assay, membranes are thawed onice for 20 minutes and then 10 mL of incubation buffer (20 mM Hepes, 1mM MgCl₂, 100 mM NaCl, pH 7.4) added. The membranes are then vortexed toresuspend the crude membrane pellet and homogenized with a BrinkmannPT-3100 Polytron homogenizer for 15 seconds at setting 6. Theconcentration of membrane protein is determined using the BRL Bradfordprotein assay.

B. Binding Assay

For total binding, a total volume of 50 ul of appropriately dilutedmembranes (diluted in assay buffer containing 50 mM Tris HCl (pH 7.4), 1mM MgCl₂, and 1 mM EDTA; 5-50 ug protein) is added to 96-wellpolyproylene microtiter plates followed by addition of 100 ul of assaybuffer and 50 ul of a radiolabeled known ligand. For nonspecificbinding, 50 ul of assay buffer is added instead of 100 ul and anadditional 50ul of 10 uM said known ligand which is not radiolabeled isadded before 50 ul of said radiolabeled known ligand is added. Platesare then incubated at room temperature for 60-120 minutes. The bindingreaction is terminated by filtering assay plates through a MicroplateDevices GF/C Unifilter filtration plate with a Brandell 96-well plateharvestor followed by washing with cold 50 mM Tris HCl, pH 7.4containing 0.9% NaCl. Then, the bottom of the filtration plate aresealed, 50 ul of Optiphase Supermix is added to each well, the top ofthe plates are sealed, and plates are counted in a Trilux MicroBetascintillation counter. For determining whether less of the complexbetween said radiolabeled known ligand and said receptor is formed inthe presence of a test compound, instead of adding 100 ul of assaybuffer, 100 ul of appropriately diluted said test compound is added toappropriate wells followed by addition of 50 ul of said radiolabledknown ligand.

A level of specific binding of the radiolabled known ligand in thepresence of the test compound less than a level of specific binding ofthe radiolabeled known ligand in the absence of the test compound isindicative of less of the complex between said radiolabeled known ligandand said receptor being formed in the presence of the test compound thanin the absence of the test compound.

Example 10

Expression of GPR119 in Gut

The expression of GPR119 mRNA in various tissues was determined usingRNase Protection Assay (RPA).

Mouse tissue RNA was obtained commercially (Clontech). A 255 bpprotected fragment of mouse GPR119 was cloned into pCRII-TOPO cloningvector (Invitrogen). The sequence of the 255 bp protected fragment wasas follows (nucleotides that comprise mouse GPR119 coding region areunderlined): 5′-CTGGCCTGCCAGTAATGGCCAGAACGGTGCTGTGACTCTGAGCCTATAGCACAT(SEQ ID NO: 5) CTAATCCTGTCCCATGAGAATCTGAGCTCGCCATCCAGCATGCCTTTGTAAGTGGAAGTGCTGCTACCTCACCATGGAGTCATCCTTCTCATTTGGAGTGATCCTTGCTGTCCTAACCATCCTCATCATTGCTGTTAATGCACTGGTAGTTGTGGCTATGCTGCTATCAATCTACAAGAATGATGGTGTTGGCCTTTGCTT-3′.

The full length probe size was 356 bp. The plasmid was linearized withBamHI and gel purified using the Sephaglass Bandprep Kit (Amersham).After gel purification of the fragment, a riboprobe was made by in vitrotranscription with using T7 RNA polymerase (Ambion Maxiscript Kit). Theprobe was purified by acrylamide gel electrophoresis and hybridized with20 ug of total RNA at 45° C. overnight. The hybrids were digested withRNAse the following day and run on a 5% acrylamide gel to detect theresults (Ambion, RPA III kit). All the procedures for in vitrotranscription and RPA reactions were following the manufacturer'sinstructions.

The highest level of GPR119 expression was found in pancreatic islets,although GPR119 was also found to be expressed in colon and to lesserextent in small intestine. See FIG. 3.

Example 11

Expression of GPR119 in GLUTag Enteroendocrine Cell Line

Northern blot analysis was used to determine the level of GPR119 mRNAexpression in GLUTag (Fla subline; see Example 12, infra), HIT-T15 (ahamster pancreatic beta cell line; ATCC No. CRL-1777), and NCI-H716 (ahuman endocrine cell line; ATCC No. CRL-251). GLUTag is a mouseenteroendocrine cell line that secretes GLP-1 [Brubaker et al.,Endocrinology (1998) 139:4108-4114].

RNA was extracted from tissue cultured cells by using RNA Bee(Tel-Test). Ten (10) μg of total RNA was separated on a 0.8% agarose gelelectrophoresis, and blotted onto nylon membrane (Amersham). The RNAblot was hybridized with a ³²P-labeled mouse GPR119 cDNA probe (see,e.g., mouse GPR119, GenBanke Accession No. AY288423), followed byreprobing with a ³²P-labeled cDNA probe for mouse preproglucagon mRNA asa control. The hybridization signals were visualized by autoradiography.

GLUTag cells (Fla subline; see Example 12, infra) were found to expressGPR119 and preproglucagon. See FIG. 4.

Example 12

GPR119 Agonist Elevates Intracellular cAMP in GLUTag Cells

GLUTag is a mouse enteroendocrine cell line that secretes GLP-1[Brubaker et al., Endocrinology (1998) 139:4108-4114]. The effect ofGPR119 agonist on the level of intracellular cAMP in GLUTag (Flasubline) enteroendocrine cells was determined. The Fro subline of GLUTagwas used as a negative control. Northern blot analysis (inset) usingmouse GPR119 cDNA as probe (see, e.g., mouse GPR119, GenBank® AccessionNo. AY288423) indicated that the Fla subline of GLUTag expresses GPR119,whereas the Flo subline of GLUTag does not detectably express GPR119.

GluTag (GLUTag-Fla and GLUTag-Fro) cells were plated at 85% confluencyin 15-cm tissue culture plate with regular growth medium. On the nextday, cells were scraped off with cold Scraping Buffer (20 mM HEPES, 10mM EDTA, pH 7.4) and spinned down at 1000 rpm for 17 mins at 4° C. Cellpellets were washed with cold Membrane Wash Buffer (20 mM HEPES, 0.1 mMEDTA, pH 7.4) and spun again as above. The membrane pellets wereresuspended in cold Binding Buffer (20 mM HEPES, 1 mM MgCl₂, 100 mMNaCl, pH 7.4) and homogenized twice using a Polytron™ homogenizer (ModelNo. PT3100; Brinkman) at 7000 rpm for 10 seconds. Protein concentrationwas determined by Bradford Assay. Cell membranes were diluted to aprotein concentration of 0.2 mg/ml in Binding Buffer. (The final assayconcentration was 10 ug/well).

The cyclase assay was done with a Flash Plate™ Adenylyl Cyclase kit (NewEngland Nuclear; Cat. No. SMP004A). The Flash Plate wells contain ascintillant coating which also contains a specific antibody recognizingcAMP. The cAMP generated in the wells can be quantitated by a directcompetition for binding of radioactive cAMP tracer to the cAMP antibody.

Details of the cyclase assay as it was carried out are described here.cAMP standards and Detection Buffer (comprising 1 μCi of tracer [125I]cAMP (50 μl) to 11 ml Detection Buffer) were prepared and maintained inaccordance with the manufacturer's instructions. GPR119 agonist AR231453was freshly prepared and serially diluted in 50 ul freshly prepared 2×Reconstitution Buffer (20 mM Phosphocreatine, 20 units/50 ul CreatinePhosphokinase, 20 uM GTP, 0.2 mM ATP, 1 mM IBMX). Eight doses of GPR119agonist, from 10 uM down to 1.27 nM, were tested. The assay was carriedout in a 96-well Flash Plate. GPR119 agonist and cAMP standards werefirst added to appropriate wells. The cell membranes were then added tothe wells, and the plate was incubated for 60 minutes at roomtemperature. 100ul of Detection Mix containing tracer ³H-cAMP was thenadded to each well. Plates were incubated for an additional two hours,after which the samples were counted in a Wallac MicroBeta scintillationcounter. Values of cAMP/well were then extrapolated from a standard cAMPcurve which was contained within each assay plate.

GPR119 agonist was found to elevate the level of intracellular cAMP inGLUTag-Fla cells which express GPR119, but not in GLUTag-Fro cells whichdo not express GPR119. GPR119 agonist was found to elevate cAMP inGLUTag cells with an EC50 of about 4.3 nM. See FIG. 5.

Example 13

GPR119 Agonist Stimulates GLP-1 Secretion in GLUTag Cells

GLUTag-Fla cells (see Example 12, supra) were plated in 24-well plateson day one in complete culture medium (DMEM/10%FBS). On day two theculture medium was replaced with a low glucose medium (DMEM/3 mMGlucose/10% FBS). On day three cells were washed twice with 1×PBS. Thewashed GLUTag-Fla cells were stimulated with GPR119 agonist (AR231453)at various concentrations or with forskolin (1 uM) as a positive controlin serum free DMEM with 15 mM glucose for one hour at 37° C. and 5%CO2in a tissue culture incubator. The supernatants were then collected andclarified by centrifugation at 500 g and 4° C. for 5 minutes. GLP-1released into the supernatant was determined by ELISA using reagentspurchased from LINCO Research Laboratory [Glucagon-Like Peptide-1(Active) ELISA Kit. Cat. # EGLP-35K].

GLUTag-Fla cells were found to secrete GLP-1 when stimulated with GPR119agonist. See FIG. 6.

Example 14 Effect of GPR119 Agonist AR244061 and DPP-IV Inhibitors inLowering Blood Glucose Level in Oral Glucose Tolerance Test (oGTT) inMice

Oral glucose tolerance test (oGTT) in 7-8 week old C57BL/6J mice wascarried out as described here. Overnight fasted mice (n=8 mice pertreatment group) were administered via oral gavage with vehicle, aGPR119 agonist (AR244061, different to that used in Example 1), a DPP-IVinhibitor (MK-0431, LAF237 or FE107542), or a combination of the GPR119agonist and the DPP-IV inhibitor. GPR119 agonist AR244061 wasadministered at 10 mpk or 30 mpk (milligram compound per kilogram ofbody weight). DPP-IV inhibitors MK-0431 and LAF237 were administered at1 mpk, and FE107542 was administered at 10 mpk. One hour after compounddosing, a glucose bolus (2 gram/kg) was delivered per orally, and tailblood samples were collected to measure blood glucose at 0, 30, 60 and120 minutes. Results obtained for MK-0431 are shown in FIG. 7; resultsobtained for LAF237 are shown in FIG. 8; and results obtained forFE107542 are shown in FIG. 9. For each treatment group, glycemicexcursion curve was graphed and is presented with blood glucoseconcentration given in mean values ± standard error of the mean (SEM).Area Under Curve (AUC) of the glycemic excursion was calculated andreported as AUC (% of vehicle control).

From inspection of FIG. 7, FIG. 8 and FIG. 9, it is apparent thatwhereas at the concentrations used both the GPR119 agonist (a GPR119agonist different to that used in Example 1) and the DPP-IV inhibitoralone (for each of three different DPP-IV inhibitors) providedmeasurable glycemic control, combination of the GPR119 agonist and theDPP-IV inhibitor provided a dose-dependent level of glycemic controlover that provided by the GPR119 agonist or DPP-IV inhibitor alone.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptions, or modifications, as come within thescope of the following claims and its equivalents.

1. A method of treating or preventing diabetes or a condition relatedthereto comprising administering to a subject in need thereof atherapeutically effective amount of a composition comprising a GPR119agonist and a DPP-IV inhibitor.
 2. A method in accordance with claim 1,wherein the GPR119 agonist and the DPP-IV inhibitor are administered inamounts sufficient to lower a blood glucose level in the subject.
 3. Amethod of treating or preventing a condition ameliorated by increasing ablood GLP-1 level comprising administering to a subject in need thereofa therapeutically effective amount of a composition comprising a GPR119agonist and a DPP-IV inhibitor.
 4. A method in accordance with claim 3,wherein the GPR119 agonist and the DPP-IV inhibitor are administered inamounts sufficient to increase a blood GLP-1 level in the subject.
 5. Amethod of increasing a blood GLP-1 level comprising administering to asubject deficient in GLP-1 a therapeutically effective amount of acomposition comprising a GPR119 agonist and a DPP-IV inhibitor.
 6. Amethod in accordance with claim 5, wherein the GPR119 agonist and theDPP-IV inhibitor are administered in amounts sufficient to increase ablood GLP-1 level in the subject.
 7. A method in accordance with claim 1or claim 2, wherein diabetes is Type 2 diabetes.
 8. A method inaccordance with claim 1 or claim 2, wherein the condition related todiabetes is selected from the group consisting of hyperglycemia,impaired glucose tolerance, insulin resistance, pancreatic beta-cellinsufficiency, enteroendocrine cell insufficiency, glucosuria, metabolicacidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, diabetic coronary artery disease, diabetic cerebrovasculardisease, diabetic peripheral vascular disease, metabolic syndrome,hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity.
 9. Amethod in accordance with claim 3 or claim 4, wherein the conditionameliorated by increasing a blood GLP-1 level is selected from the groupconsisting of diabetes, a condition related to diabetes, myocardialinfarction, learning impairment, memory impairment, and aneurodegenerative disorder.
 10. A method in accordance with claim 3 orclaim 4, wherein the condition ameliorated by increasing a blood GLP-1level is a neurodegenerative disorder selected from the group consistingof excitotoxic brain damage caused by severe epileptic seizures,Alzheimer's disease, Parkinson's disease, Huntington's disease,prion-associated disease, stroke, motor-neuron disease, learning ormemory impairment, traumatic brain injury, spinal cord injury, andperipheral neuropathy.
 11. A method in accordance with any one of claims1, 3, and 5, wherein the subject is a human.
 12. A compositioncomprising a GPR119 agonist and a DPP-IV inhibitor.
 13. A dosage form ofa composition in accordance with claim 12, wherein the GPR119 agonistand the DPP-IV inhibitor are in amounts sufficient to lower a bloodglucose level in a subject.
 14. A dosage form of a composition inaccordance with claim 12, wherein the GPR119 agonist and the DPP-IVinhibitor are in amounts sufficient to increase a blood GLP-1 level in asubject.
 15. A dosage form in accordance with claim 13 or 14, where thesubject is human.
 16. A composition comprising a GPR119 agonist and aDPP-IV inhibitor, for use in a method of treatment of the human oranimal body by therapy.
 17. A composition in accordance with claim 16,wherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to lower a blood glucose level in a subject.
 18. Acomposition in accordance with claim 16, wherein the GPR119 agonist andthe DPP-IV inhibitor are in amounts to increase a blood GLP-1 level in asubject.
 19. A method of preparing a pharmaceutical composition, saidmethod comprising admixing a GPR119 agonist and a DPP-IV inhibitor,together with at least one pharmaceutically acceptable carrier.
 20. Amethod in accordance with claim 19, said method further comprising thestep of preparing a dosage form of the pharmaceutical compositionwherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to lower a blood glucose level in a subject.
 21. A method inaccordance with claim 19, said method further comprising the step ofpreparing a dosage form of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient toincrease a blood GLP-1 level in a subject.
 22. A pharmaceuticalcomposition comprising a GPR119 agonist and a DPP-IV inhibitor, togetherwith at least one pharmaceutically acceptable carrier.
 23. A dosage formof a pharmaceutical composition in accordance with claim 22, wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient tolower a blood glucose level in a subject.
 24. A dosage form of apharmaceutical composition in accordance with claim 22, wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient toincrease a blood GLP-1 level in a subject.
 25. A method of treating orpreventing diabetes or a condition related thereto comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a pharmaceutical composition in accordance with claim 22 orclaim
 23. 26. A method in accordance with claim 25, wherein the GPR119agonist and the DPP-IV inhibitor are in amounts sufficient to lower ablood glucose level in the subject.
 27. A method of treating orpreventing a condition ameliorated by increasing a blood GLP-1 levelcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a pharmaceutical composition in accordance withclaim 22 or claim
 24. 28. A method of increasing a blood GLP-1 levelcomprising administering to a subject deficient in GLP-1 atherapeutically effective amount of a pharmaceutical composition inaccordance with claim 22 or claim
 24. 29. A method in accordance withclaim 27 or claim 28, wherein the GPR119 agonist and the DPP-IVinhibitor are in amounts sufficient to increase a blood GLP-1 level inthe subject.
 30. A method in accordance with claim 20 or 21, wherein thesubject is a human.
 31. A method in accordance with claim 25, whereinthe subject is human.
 32. A method in accordance with claim 27, whereinthe subject is human.
 33. A method in accordance with claim 28, whereinthe subject is human
 34. A dosage form in accordance with claim 23 or24, wherein the subject is a human.
 35. A method for identifying GLP-1secretagogues or compounds useful for treating or preventing a conditionameliorated by increasing a blood GLP-1 level, comprising the steps of:(a) contacting a test compound with a host cell or with membrane of ahost cell that expresses a G protein-coupled receptor, wherein the Gprotein-coupled receptor comprises an amino acid sequence selected fromthe group consisting of: (i) amino acids 1-335 of SEQ ID NO:2; (ii)amino acids 2-335 of SEQ ID NO:2; (iii) amino acids 2-335 of SEQ IDNO:2, with the proviso that the receptor does not comprise the aminoacid sequence of SEQ ID NO:2; (iv) the amino acid sequence of a Gprotein-coupled receptor encoded by a polynucleotide comprising anucleotide sequence, said nucleotide sequence being the sequenceobtainable by a process comprising performing polymerase chain reaction(PCR) on a human DNA sample using specific primers SEQ ID NO:3 and SEQID NO:4; (v) the amino acid sequence of a G protein-coupled receptorencoded by a polynucleotide comprising a nucleotide sequence, saidnucleotide sequence hybridizing under stringent conditions to thecomplement of SEQ ID NO:]; and (vi) a biologically active fragment ofany one of (i) to (v); and (b) determining the ability of the testcompound to stimulate functionality of the receptor; wherein the abilityof the test compound to stimulate functionality of the receptor isindicative of the test compound being a GLP-1 secretagogue or a compounduseful for preventing or treating a condition ameliorated by increasinga blood GLP-1 level.
 36. A method for identifying GLP-1 secretagogues orcompounds useful for treating or preventing a condition ameliorated byincreasing a blood GLP-1 level, comprising the steps of the method ofclaim 35, and further comprising: (c) contacting a compound whichstimulates functionality of the receptor in step (b) in vitro with amammalian enteroendocrine cell; and (d) determining whether the compoundstimulates GLP-1 secretion from the mammalian enteroendocrine cell;wherein the ability of the test compound to stimulate GLP-1 secretionfrom the mammalian enteroendocrine cell is indicative of the testcompound being a GLP-1 secretagogue or a compound useful for treating orpreventing a condition ameliorated by increasing a blood GLP-1 level.37. A method for identifying GLP-1 secretagogues or compounds useful fortreating or preventing a condition ameliorated by increasing a bloodGLP-1 level, comprising the steps of the method of claim 35, and furthercomprising: (c) administering a compound which stimulates functionalityof the receptor in step (b) to a mammal; and (d) determining whether thecompound increases a blood GLP-1 level in the mammal; wherein theability of the test compound to increase a blood GLP-1 level in themammal is indicative of the test compound being a GLP-1 secretagogue ora compound useful for treating or preventing a condition ameliorated byincreasing a blood GLP-1 level.
 38. A method in accordance with claim37, wherein the mammal is a non-human mammal.
 39. A method in accordancewith claim 35, wherein the host cell comprises an expression vector,said expression vector comprising a polynucleotide encoding the Gprotein-coupled receptor.
 40. A method in accordance with claim 35,wherein said determining is through the measurement of the level of asecond messenger selected from the group consisting of cyclic AMP(cAMP), cyclic GMP (cGMP), inositol 1,4,5-triphosphate (IP3),diacylglycerol (DAG), MAP kinase activity, MAPK/ERK kinase kinase-1(MEKK1) activity, and Ca2+.
 41. A method in accordance with claim 40,wherein a level of cAMP is increased.
 42. A method in accordance withclaim 35, wherein said determining is through the use of a Melanophoreassay, or through the measurement of GTPγS binding to a membranecomprising said GPCR.
 43. A method for identifying GLP-1 secretagoguesor compounds useful for treating or preventing a condition amelioratedby increasing a blood GLP-1 level, comprising the steps of: (a)contacting a G protein-coupled receptor with an optionally labeled knownligand to the receptor in the presence or absence of a test compound,wherein the G protein-coupled receptor comprises an amino acid sequenceselected from the group consisting of: (i) amino acids 1-335 of SEQ IDNO:2; (ii) amino acids 2-335 of SEQ ID NO:2; (iii) amino acids 2-335 ofSEQ ID NO:2, with the proviso that the receptor does not comprise theamino acid sequence of SEQ ID NO:2; (iv) the amino acid sequence of a Gprotein-coupled receptor encoded by a polynucleotide comprising anucleotide sequence, said nucleotide sequence being the sequenceobtainable by a process comprising performing polymerase chain reaction(PCR) on a human DNA sample using specific primers SEQ ID NO:3 and SEQID NO:4; (v) the amino acid sequence of a G protein-coupled receptorencoded by a polynucleotide comprising a nucleotide sequence, saidnucleotide sequence hybridizing under stringent conditions to thecomplement of SEQ ID NO:1; and (vi) a biologically active fragment ofany one of (i) to (v); and (b) detecting the complex between said knownligand and said receptor; and (c) determining whether less of saidcomplex is formed in the presence of the test compound than in theabsence of the test compound; wherein said determination is indicativeof the test compound being a GLP-1 secretagogue or a compound useful forpreventing or treating a condition ameliorated by increasing a bloodGLP-1 level.
 44. A method for identifying GLP-1 secretagogues orcompounds useful for treating or preventing a condition ameliorated byincreasing a blood GLP-1 level, comprising the steps of the method ofclaim 43, and further comprising: (d) contacting a compound in thepresence of which less of said complex is formed in step (c) in vitrowith a mammalian enteroendocrine cell; and (e) determining whether thecompound stimulates GLP-1 secretion from the mammalian enteroendocrinecell; wherein the ability of the test compound to stimulate GLP-1secretion from the mammalian enteroendocrine cell is indicative of thetest compound being a GLP-1 secretagogue or a compound useful forpreventing or treating a condition ameliorated by increasing a bloodGLP-1 level.
 45. A method for identifying GLP-1 secretagogues orcompounds useful for treating or preventing a condition ameliorated byincreasing a blood GLP-1 level, comprising the steps of the method ofclaim 43, and further comprising: (d) administering a compound in thepresence of which less of said complex is formed in step (c) to amammal; and (e) determining whether the compound increases a blood GLP-1level in the mammal; wherein the ability of the test compound toincrease a blood GLP-1 level in the mammal is indicative of the testcompound being a GLP-1 secretagogue or a compound useful for treating orpreventing a condition ameliorated by increasing a blood GLP-1 level.46. A method in accordance with claim 45, wherein the mammal is anon-human mammal.
 47. The method in accordance with claim 43, whereinthe receptor is recombinant.